Targeted Protein Degradation of Metalloenzymes
Methods in Drug Discovery and Discovering Lead Molecules
Conor B. O'Herin,
Seth M. Cohen,
Conor B. O'Herin
University of California, San Diego, La Jolla, CA, USA
Search for more papers by this authorSeth M. Cohen
University of California, San Diego, La Jolla, CA, USA
Search for more papers by this authorConor B. O'Herin,
Seth M. Cohen,
Conor B. O'Herin
University of California, San Diego, La Jolla, CA, USA
Search for more papers by this authorSeth M. Cohen
University of California, San Diego, La Jolla, CA, USA
Search for more papers by this authorFirst published: 26 May 2025
Abstract
The field of targeted protein degradation (TPD) has expanded rapidly in the last decade. However, only a handful of metal-dependent enzymes (metalloenzymes) have been the target of these efforts. The chapter gives an overview of TPD as it has been applied to metalloenzymes and highlights key findings. The relevant bioinorganic chemistry of these approaches, including the metal-binding pharmacophores (MBPs) used in these degraders, will be a particular emphasis in this review.
References
- 1Waldron, K.J., Rutherford, J.C., Ford, D., and Robinson, N.J. (2009). Metalloproteins and metal sensing. Nature 460: 823–830.
- 2Torres, E. and Ayala, M. (2013). 6.24 – Biocatalysis by metalloenzymes. In: Comprehensive Inorganic Chemistry II, 2e (ed. J. Reedijk and K. Poeppelmeier). Amsterdam: Elsevier.
10.1016/B978-0-08-097774-4.00625-2 Google Scholar
- 3White, R.J., Margolis, P.S., Trias, J., and Yuan, Z. (2003). Targeting metalloenzymes: A strategy that works. Curr. Opin. Pharmacol. 3: 502–507.
- 4Chen, A.Y., Adamek, R.N., Dick, B.L., Credille, C.V., Morrison, C.N., and Cohen, S.M. (2019). Targeting metalloenzymes for therapeutic intervention. Chem. Rev. 119: 1323–1455.
- 5Credille, C.V., Morrison, C.N., Stokes, R.W., Dick, B.L., Feng, Y., Sun, J., Chen, Y., and Cohen, S.M. (2019). SAR exploration of tight-binding inhibitors of influenza virus PA endonuclease. J. Med. Chem. 62: 9438–9449.
- 6Whittaker, M., Floyd, C.D., Brown, P., and Gearing, A.J.H. (1999). Design and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev. 99: 2735–2776.
- 7Li, G., Su, Y., Yan, Y.-H., Peng, J.-Y., Dai, Q.-Q., Ning, X.-L., Zhu, C.-L., Fu, C., Mcdonough, M.A., Schofield, C.J., Huang, C., and Li, G.-B. (2019). MeLAD: An integrated resource for metalloenzyme-ligand associations. Bioinformatics 36: 904–909.
- 8Yu, J.-L., Wu, S., Zhou, C., Dai, Q.-Q., Schofield, C.J., and Li, G.-B. (2022). MeDBA: The metalloenzyme data bank and analysis platform. Nucleic Acids Res. 51: D593–D602.
10.1093/nar/gkac860 Google Scholar
- 9Jacobsen, J.A., Fullagar, J.L., Miller, M.T., Salam, N.K., and Cohen, S.M. (2010). Identifying chelators for metalloprotein inhibitors using a fragment-based approach. J. Med. Chem. 54: 591–602.
- 10Dick, B.L. and Cohen, S.M. (2018). Metal-binding isosteres as new scaffolds for metalloenzyme inhibitors. Inorg. Chem. 57: 9538–9543.
- 11Dick, B.L., Patel, A., and Cohen, S.M. (2020). Effect of heterocycle content on metal binding isostere coordination. Chem. Sci. 11: 6907–6914.
- 12Seo, H., Jackl, M.K., Kalaj, M., and Cohen, S.M. (2022). Developing metal-binding isosteres of 8-hydroxyquinoline as metalloenzyme inhibitor scaffolds. Inorg. Chem. 61: 7631–7641.
- 13Seo, H., Kohlbrand, A.J., Stokes, R.W., Chung, J., and Cohen, S.M. (2023). Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs. Chem. Commun. 59: 2283–2286.
- 14Békés, M., Langley, D.R., and Crews, C.M. (2022). PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug Discov. 21: 181–200.
- 15Lai, A.C. and Crews, C.M. (2017). Induced protein degradation: An emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16: 101–114.
- 16Bassi, Z.I., Fillmore, M.C., Miah, A.H., Chapman, T.D., Maller, C., Roberts, E.J., Davis, L.C., Lewis, D.E., Galwey, N.W., Waddington, K.E., Parravicini, V., Macmillan-Jones, A.L., Gongora, C., Humphreys, P.G., Churcher, I., Prinjha, R.K., and Tough, D.F. (2018). Modulating PCAF/GCN5 immune cell function through a PROTAC approach. ACS Chem. Biol. 13: 2862–2867.
- 17Sun, X., Wang, J., Yao, X., Zheng, W., Mao, Y., Lan, T., Wang, L., Sun, Y., Zhang, X., Zhao, Q., Zhao, J., Xiao, R.-P., Zhang, X., Ji, G., and Rao, Y. (2019). A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 5: 10.
- 18Kleiger, G. and Mayor, T. (2014). Perilous journey: A tour of the ubiquitin–proteasome system. Trends Cell Biol. 24: 352–359.
- 19Ciechanover, A., Orian, A., and Schwartz, A.L. (2000). Ubiquitin-mediated proteolysis: Biological regulation via destruction. BioEssays 22: 442–451.
10.1002/(SICI)1521-1878(200005)22:5<442::AID-BIES6>3.0.CO;2-Q CAS PubMed Web of Science® Google Scholar
- 20Burslem, G.M. and Crews, C.M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181: 102–114.
- 21Schapira, M., Calabrese, M.F., Bullock, A.N., and Crews, C.M. (2019). Targeted protein degradation: Expanding the toolbox. Nat. Rev. Drug Discov. 18: 949–963.
- 22Shah Zaib Saleem, R., Schwalm, M.P., and Knapp, S. (2024). Expanding the ligand spaces for E3 ligases for the design of protein degraders. Bioorg. Med. Chem. 105: 117718.
- 23Cyrus, K., Wehenkel, M., Choi, E.-Y., Han, H.-J., Lee, H., Swanson, H., and Kim, K.-B. (2011). Impact of linker length on the activity of PROTACs. Mol. BioSyst. 7: 359–364.
- 24Nowak, R.P., Deangelo, S.L., Buckley, D., He, Z., Donovan, K.A., An, J., Safaee, N., Jedrychowski, M.P., Ponthier, C.M., Ishoey, M., Zhang, T., Mancias, J.D., Gray, N.S., Bradner, J.E., and Fischer, E.S. (2018). Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14: 706–714.
- 25Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K.A., Ding, W., Schiemer, J., Feng, X., Chang, J.S., Uccello, D.P., Young, J.A., Garcia-Irrizary, C.N., Czabaniuk, L., Schuff, B., Oliver, R., Montgomery, J., Hayward, M.M., Coe, J., Chen, J., Niosi, M., Luthra, S., Shah, J.C., El-Kattan, A., Qiu, X., West, G.M., Noe, M.C., Shanmugasundaram, V., Gilbert, A.M., Brown, M.F., and Calabrese, M.F. (2018). Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc. Natl. Acad. Sci. 115: E7285–E7292.
- 26Bondeson, D.P., Smith, B.E., Burslem, G.M., Buhimschi, A.D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B.D., Ishchenko, A., and Crews, C.M. (2018). Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25: 78–87.e5.
- 27Gadd, M.S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D.J., Zengerle, M., and Ciulli, A. (2017). Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13: 514–521.
- 28Park, D., Izaguirre, J., Coffey, R., and Xu, H. (2023). Modeling the effect of cooperativity in ternary complex formation and targeted protein degradation mediated by heterobifunctional degraders. ACS Bio. Med. Chem. Au 3: 74–86.
- 29Wurz, R.P., Rui, H., Dellamaggiore, K., Ghimire-Rijal, S., Choi, K., Smither, K., Amegadzie, A., Chen, N., Li, X., Banerjee, A., Chen, Q., Mohl, D., and Vaish, A. (2023). Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation. Nat. Commun. 14: 4177.
- 30Bondeson, D.P., Mares, A., Smith, I.E., Ko, E., Campos, S., Miah, A.H., Mulholland, K.E., Routly, N., Buckley, D.L., Gustafson, J.L., Zinn, N., Grandi, P., Shimamura, S., Bergamini, G., Faelth-Savitski, M., Bantscheff, M., Cox, C., Gordon, D.A., Willard, R.R., Flanagan, J.J., Casillas, L.N., Votta, B.J., Den Besten, W., Famm, K., Kruidenier, L., Carter, P.S., Harling, J.D., Churcher, I., and Crews, C.M. (2015). Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11: 611–617.
- 31He, X., Weng, Z., and Zou, Y. (2024). Progress in the controllability technology of PROTAC. Eur. J. Med. Chem. 265: 116096.
- 32Hamilton, E.P., Ma, C., De Laurentiis, M., Iwata, H., Hurvitz, S.A., Wander, S.A., Danso, M., Lu, D.R., Perkins Smith, J., Liu, Y., Tran, L., Anderson, S., and Campone, M. (2024). VERITAC-2: A Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer. Future Oncol. 20: 2447–2455.
- 33Bemis, T.A., La Clair, J.J., and Burkart, M.D. (2021). Unraveling the role of linker design in proteolysis targeting chimeras. J. Med. Chem. 64: 8042–8052.
- 34Cecchini, C., Pannilunghi, S., Tardy, S., and Scapozza, L. (2021). From conception to development: Investigating PROTACs features for improved cell permeability and successful protein degradation. Front. Chem. 9: 672267.
- 35Edmondson, S.D., Yang, B., and Fallan, C. (2019). Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges. Bioorg. Med. Chem. Lett. 29: 1555–1564.
- 36Riching, K.M., Caine, E.A., Urh, M., and Daniels, D.L. (2022). The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation. Chem. Soc. Rev. 51: 6210–6221.
- 37Rodriguez-Rivera, F.P. and Levi, S.M. (2021). Unifying catalysis framework to dissect proteasomal degradation paradigms. ACS Central Sci. 7: 1117–1125.
- 38Ottis, P., Palladino, C., Thienger, P., Britschgi, A., Heichinger, C., Berrera, M., Julien-Laferriere, A., Roudnicky, F., Kam-Thong, T., Bischoff, J.R., Martoglio, B., and Pettazzoni, P. (2019). Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem. Biol. 14: 2215–2223.
- 39Shirasaki, R., Matthews, G.M., Gandolfi, S., De Matos Simoes, R., Buckley, D.L., Raja Vora, J., Sievers, Q.L., Brüggenthies, J.B., Dashevsky, O., Poarch, H., Tang, H., Bariteau, M.A., Sheffer, M., Hu, Y., Downey-Kopyscinski, S.L., Hengeveld, P.J., Glassner, B.J., Dhimolea, E., Ott, C.J., Zhang, T., Kwiatkowski, N.P., Laubach, J.P., Schlossman, R.L., Richardson, P.G., Culhane, A.C., Groen, R.W.J., Fischer, E.S., Vazquez, F., Tsherniak, A., Hahn, W.C., Levy, J., Auclair, D., Licht, J.D., Keats, J.J., Boise, L.H., Ebert, B.L., Bradner, J.E., Gray, N.S., and Mitsiades, C.S. (2021). Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep. 34: 108532.
- 40Zhang, L., Riley-Gillis, B., Vijay, P., and Shen, Y. (2019). Acquired resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol. Cancer Ther. 18: 1302–1311.
- 41Xie, S., Zhu, J., Li, J., Zhan, F., Yao, H., Xu, J., and Xu, S. (2023). Small-molecule hydrophobic tagging: A promising strategy of druglike technology for targeted protein degradation. J. Med. Chem. 66: 10917–10933.
- 42He, Q., Zhao, X., Wu, D., Jia, S., Liu, C., Cheng, Z., Huang, F., Chen, Y., Lu, T., and Lu, S. (2023). Hydrophobic tag-based protein degradation: Development, opportunity and challenge. Eur. J. Med. Chem. 260: 115741.
- 43Cromm, P.M., Samarasinghe, K.T.G., Hines, J., and Crews, C.M. (2018). Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J. Am. Chem. Soc. 140: 17019–17026.
- 44Mares, A., Miah, A.H., Smith, I.E., Rackham, M., Thawani, A.R., Cryan, J., Haile, P.A., Votta, B.J., Beal, A.M., and Capriotti, C. (2020). Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3: 140.
- 45You, I., Erickson, E.C., Donovan, K.A., Eleuteri, N.A., Fischer, E.S., Gray, N.S., and Toker, A. (2020). Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem. Biol. 27: 66–73.e7.
- 46Smith, B.E., Wang, S.L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B.D., and Crews, C.M. (2019). Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 10: 131.
- 47Durham, T.B. and Blanco, M.-J. (2015). Target engagement in lead generation. Bioorg. Med. Chem. Lett. 25: 998–1008.
- 48Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K.T.G., Vogt, L., Rosen, N., and Crews, C.M. (2021). Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 12: 920.
- 49Yang, K., Song, Y., Xie, H., Wu, H., Wu, Y.T., Leisten, E.D., and Tang, W. (2018). Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg. Med. Chem. Lett. 28: 2493–2497.
- 50Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., Liu, X., Thummuri, D., Yuan, Y., Wiegand, J.S., Pei, J., Zhang, W., Sharma, A., Mccurdy, C.R., Kuruvilla, V.M., Baran, N., Ferrando, A.A., Kim, Y.-M., Rogojina, A., Houghton, P.J., Huang, G., Hromas, R., Konopleva, M., Zheng, G., and Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25: 1938–1947.
- 51Verdin, E. and Ott, M. (2015). 50 years of protein acetylation: From gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16: 258–264.
- 52Bannister, A.J. and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Res. 21: 381–395.
- 53Pérez-Salvia, M. and Esteller, M. (2017). Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics 12: 323–339.
- 54Allfrey, V.G., Faulkner, R., and Mirsky, A. (1964). Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl. Acad. Sci. 51: 786–794.
- 55Glozak, M.A., Sengupta, N., Zhang, X., and Seto, E. (2005). Acetylation and deacetylation of non-histone proteins. Gene 363: 15–23.
- 56Narita, T., Weinert, B.T., and Choudhary, C. (2019). Functions and mechanisms of non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 20: 156–174.
- 57Kutil, Z., Novakova, Z., Meleshin, M., Mikesova, J., Schutkowski, M., and Barinka, C. (2018). Histone deacetylase 11 Is a fatty-acid deacylase. ACS Chem. Biol. 13: 685–693.
- 58Mcclure, J.J., Inks, E.S., Zhang, C., Peterson, Y.K., Li, J., Chundru, K., Lee, B., Buchanan, A., Miao, S., and Chou, C.J. (2017). Comparison of the deacylase and deacetylase activity of zinc-dependent HDACs. ACS Chem. Biol. 12: 1644–1655.
- 59Porter, N.J. and Christianson, D.W. (2019). Structure, mechanism, and inhibition of the zinc-dependent histone deacetylases. Curr. Opin. Struct. Biol. 59: 9–18.
- 60Ganesan, A. (2020). Targeting the zinc-dependent histone deacetylases (HDACs) for drug discovery. In: Chemical Epigenetics (ed. A. MAI). Cham: Springer International Publishing.
- 61Hong, J.Y., Jing, H., Price, I.R., Cao, J., Bai, J.J., and Lin, H. (2020). Simultaneous inhibition of SIRT2 deacetylase and defatty-acylase activities via a PROTAC strategy. ACS Med. Chem. Lett. 11: 2305–2311.
- 62Schiedel, M., Herp, D., Hammelmann, S., Swyter, S., Lehotzky, A., Robaa, D., Oláh, J., Ovádi, J., Sippl, W., and Jung, M. (2018). Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals). J. Med. Chem. 61: 482–491.
- 63Ho, T.C.S., Chan, A.H.Y., and Ganesan, A. (2020). Thirty years of HDAC inhibitors: 2020 insight and hindsight. J. Med. Chem. 63: 12460–12484.
- 64Yang, F., Zhao, N., Ge, D., and Chen, Y. (2019). Next-generation of selective histone deacetylase inhibitors. RSC Adv. 9: 19571–19583.
- 65Asmamaw, M.D., He, A., Zhang, L.-R., Liu, H.-M., and Gao, Y. (2024). Histone deacetylase complexes: Structure, regulation and function. Biochim. Biophys. Acta (BBA) – Rev. Cancer 1879: 189150.
- 66Patel, U., Smalley, J.P., and Hodgkinson, J.T. (2023). PROTAC chemical probes for histone deacetylase enzymes. RSC Chem. Biol. 4: 623–634.
- 67Fischer, F., Avelar, L.A.A., Murray, L., and Kurz, T. (2022). Designing HDAC-PROTACs: Lessons learned so far. Future Med. Chem. 14: 143–166.
- 68Huang, Z., Li, L., Cheng, B., and Li, D. (2024). Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies. Biomed. Pharmacother. 178: 117218.
- 69An, Z., Lv, W., Su, S., Wu, W., and Rao, Y. (2019). Developing potent PROTACs tools for selective degradation of HDAC6 protein. Protein Cell 10: 606–609.
- 70Yang, H., Lv, W., He, M., Deng, H., Li, H., Wu, W., and Rao, Y. (2019). Plasticity in designing PROTACs for selective and potent degradation of HDAC6. Chem. Commun. 55: 14848–14851.
- 71Wu, H., Yang, K., Zhang, Z., Leisten, E.D., Li, Z., Xie, H., Liu, J., Smith, K.A., Novakova, Z., Barinka, C., and Tang, W. (2019). Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J. Med. Chem. 62: 7042–7057.
- 72Yang, K., Wu, H., Zhang, Z., Leisten, E.D., Nie, X., Liu, B., Wen, Z., Zhang, J., Cunningham, M.D., and Tang, W. (2020). Development of selective histone deacetylase 6 (HDAC6) degraders recruiting von Hippel–Lindau (VHL) E3 ubiquitin ligase. ACS Med. Chem. Lett. 11: 575–581.
- 73Yang, K., Zhao, Y., Nie, X., Wu, H., Wang, B., Almodovar-Rivera, C.M., Xie, H., and Tang, W. (2020). A cell-based target engagement assay for the identification of cereblon E3 ubiquitin ligase ligands and their application in HDAC6 degraders. Cell Chem. Biol. 27: 866–876.
- 74Chakrabarti, A., Oehme, I., Witt, O., Oliveira, G., Sippl, W., Romier, C., Pierce, R.J., and Jung, M. (2015). HDAC8: A multifaceted target for therapeutic interventions. Trends Pharmacol. Sci. 36: 481–492.
- 75Zhao, Q., Liu, H., Peng, J., Niu, H., Liu, J., Xue, H., Liu, W., Liu, X., Hao, H., Zhang, X., and Wu, J. (2024). HDAC8 as a target in drug discovery: Function, structure and design. Eur. J. Med. Chem. 280: 116972.
- 76Marek, M., Shaik, T.B., Heimburg, T., Chakrabarti, A., Lancelot, J., Ramos-Morales, E., Da Veiga, C., Kalinin, D., Melesina, J., Robaa, D., Schmidtkunz, K., Suzuki, T., Holl, R., Ennifar, E., Pierce, R.J., Jung, M., Sippl, W., and Romier, C. (2018). Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants. J. Med. Chem. 61: 10000–10016.
- 77Chotitumnavee, J., Yamashita, Y., Takahashi, Y., Takada, Y., Iida, T., Oba, M., Itoh, Y., and Suzuki, T. (2022). Selective degradation of histone deacetylase 8 mediated by a proteolysis targeting chimera (PROTAC). Chem. Commun. 58: 4635–4638.
- 78Darwish, S., Ghazy, E., Heimburg, T., Herp, D., Zeyen, P., Salem-Altintas, R., Ridinger, J., Robaa, D., Schmidtkunz, K., Erdmann, F., Schmidt, M., Romier, C., Jung, M., Oehme, I., and Sippl, W. (2022). Design, synthesis and biological characterization of histone deacetylase 8 (HDAC8) proteolysis targeting chimeras (PROTACs) with anti-neuroblastoma activity. Int. J. Mol. Sci. 23: 7535.
- 79Sun, Z., Deng, B., Yang, Z., Mai, R., Huang, J., Ma, Z., Chen, T., and Chen, J. (2022). Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8. Eur. J. Med. Chem. 239: 114544.
- 80Huang, J., Zhang, J., Xu, W., Wu, Q., Zeng, R., Liu, Z., Tao, W., Chen, Q., Wang, Y., and Zhu, W.-G. (2023). Structure-based discovery of selective histone deacetylase 8 degraders with potent anticancer activity. J. Med. Chem. 66: 1186–1209.
- 81Zhao, C., Chen, D., Suo, F., Setroikromo, R., Quax, W.J., and Dekker, F.J. (2023). Discovery of highly potent HDAC8 PROTACs with anti-tumor activity. Bioorg. Chem. 136: 106546.
- 82Kelly, R.D.W. and Cowley, S.M. (2013). The physiological roles of histone deacetylase (HDAC) 1 and 2: Complex co-stars with multiple leading parts. Biochem. Soc. Trans. 41: 741–749.
- 83Feller, F. and Hansen, F.K. (2023). Targeted protein degradation of histone deacetylases by hydrophobically tagged inhibitors. ACS Med. Chem. Lett. 14: 1863–1868.
- 84Sinatra, L., Bandolik, J.J., Roatsch, M., Sönnichsen, M., Schoeder, C.T., Hamacher, A., Schöler, A., Borkhardt, A., Meiler, J., Bhatia, S., Kassack, M.U., and Hansen, F.K. (2020). Hydroxamic acids immobilized on resins (HAIRs): Synthesis of dual-targeting HDAC inhibitors and HDAC degraders (PROTACs). Angew. Chem. Int. Ed. 59: 22494–22499.
- 85Shen, S. and Kozikowski, A.P. (2016). Why hydroxamates may not be the best histone deacetylase inhibitors—What some may have forgotten or would rather forget? ChemMedChem 11: 15–21.
- 86Geurs, S., Clarisse, D., De Bosscher, K., and D'hooghe, M. (2023). The zinc-binding group effect: Lessons from non-hydroxamic acid vorinostat analogs. J. Med. Chem. 66: 7698–7729.
- 87Bressi, J.C., Jennings, A.J., Skene, R., Wu, Y., Melkus, R., Jong, R.D., O'Connell, S., Grimshaw, C.E., Navre, M., and Gangloff, A.R. (2010). Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg. Med. Chem. Lett. 20: 3142–3145.
- 88Jamaladdin, S., Kelly, R.D.W., O'Regan, L., Dovey, O.M., Hodson, G.E., Millard, C.J., Portolano, N., Fry, A.M., Schwabe, J.W.R., and Cowley, S.M. (2014). Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells. Proc. Natl. Acad. Sci. 111: 9840–9845.
- 89Millard, C.J., Watson, P.J., Fairall, L., and Schwabe, J.W.R. (2017). Targeting class I histone deacetylases in a “complex” environment. Trends Pharmacol. Sci. 38: 363–377.
- 90Smalley, J.P., Adams, G.E., Millard, C.J., Song, Y., Norris, J.K.S., Schwabe, J.W.R., Cowley, S.M., and Hodgkinson, J.T. (2020). PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes. Chem. Commun. 56: 4476–4479.
- 91Cao, F., De Weerd, S., Chen, D., Zwinderman, M.R.H., Van Der Wouden, P.E., and Dekker, F.J. (2020). Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC). Eur. J. Med. Chem. 208: 112800.
- 92Cross, J.M., Coulson, M.E., Smalley, J.P., Pytel, W.A., Ismail, O., Trory, J.S., Cowley, S.M., and Hodgkinson, J.T. (2022). A ‘click’ chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras. RSC Med. Chem. 13: 1634–1639.
- 93Smalley, J.P., Baker, I.M., Pytel, W.A., Lin, L.-Y., Bowman, K.J., Schwabe, J.W.R., Cowley, S.M., and Hodgkinson, J.T. (2022). Optimization of class I histone deacetylase PROTACs reveals that HDAC1/2 degradation is critical to induce apoptosis and cell arrest in cancer cells. J. Med. Chem. 65: 5642–5659.
- 94Baker, I.M., Smalley, J.P., Sabat, K.A., Hodgkinson, J.T., and Cowley, S.M. (2023). Comprehensive transcriptomic analysis of novel class I HDAC proteolysis targeting chimeras (PROTACs). Biochemistry 62: 645–656.
- 95König, B. and Hansen, F.K. (2024). 2-(Difluoromethyl)-1,3,4-oxadiazoles: The future of selective histone deacetylase 6 modulation? ACS Pharmacol. Transl. Sci. 7: 899–903.
- 96König, B., Watson, P.R., Reßing, N., Cragin, A.D., Schäker-Hübner, L., Christianson, D.W., and Hansen, F.K. (2023). Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6. J. Med. Chem. 66: 13821–13837.
- 97Motlová, L., Šnajdr, I., Kutil, Z., Andris, E., Ptáček, J., Novotná, A., Nováková, Z., Havlínová, B., Tueckmantel, W., Dráberová, H., Majer, P., Schutkowski, M., Kozikowski, A., Rulíšek, L., and Bařinka, C. (2023). Comprehensive mechanistic view of the hydrolysis of oxadiazole-based inhibitors by histone deacetylase 6 (HDAC6). ACS Chem. Biol. 18: 1594–1610.
- 98Cellupica, E., Gaiassi, A., Rocchio, I., Rovelli, G., Pomarico, R., Sandrone, G., Caprini, G., Cordella, P., Cukier, C., Fossati, G., Marchini, M., Bebel, A., Airoldi, C., Palmioli, A., Stevenazzi, A., Steinkühler, C., and Vergani, B. (2024). Mechanistic and structural insights on difluoromethyl-1,3,4-oxadiazole inhibitors of HDAC6. Int. J. Mol. Sci. 25: 5885.
- 99Keuler, T., König, B., Bückreiß, N., Kraft, F.B., König, P., Schäker-Hübner, L., Steinebach, C., Bendas, G., Gütschow, M., and Hansen, F.K. (2022). Development of the first non-hydroxamate selective HDAC6 degraders. Chem. Commun. 58: 11087–11090.
- 100Guenther, M.G., Barak, O., and Lazar, M.A. (2001). The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21: 6091–6101.
- 101Sun, Z., Feng, D., Fang, B., Mullican, S.E., You, S.-H., Lim, H.-W., Everett, L.J., Nabel, C.S., Li, Y., Selvakumaran, V., Won, K.-J., and Lazar, M.A. (2013). Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor. Mol. Cell 52: 769–782.
- 102Yao, Y.-L. and Yang, W.-M. (2011). Beyond histone and deacetylase: An overview of cytoplasmic histone deacetylases and their nonhistone substrates. Biomed. Res. Int. 2011: 146493.
10.1155/2011/146493 Google Scholar
- 103Xiao, Y., Wang, J., Zhao, L.Y., Chen, X., Zheng, G., Zhang, X., and Liao, D. (2020). Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs. Chem. Commun. 56: 9866–9869.
- 104Xiao, Y., Hale, S., Awasthee, N., Meng, C., Zhang, X., Liu, Y., Ding, H., Huo, Z., Lv, D., Zhang, W., He, M., Zheng, G., and Liao, D. (2023). HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation. Cell Chem. Biol. 30: 1421–1435.e12.
- 105Xiao, Y., Awasthee, N., Liu, Y., Meng, C., He, M.Y., Hale, S., Karki, R., Lin, Z., Mosterio, M., Garcia, B.A., Kridel, R., Liao, D., and Zheng, G. (2024). Discovery of a highly potent and slective HDAC8 degrader: Advancing the functional understanding and therapeutic potential of HDAC8. J. Med. Chem. 67: 12784–12806.
- 106Whitehead, L., Dobler, M.R., Radetich, B., Zhu, Y., Atadja, P.W., Claiborne, T., Grob, J.E., Mcriner, A., Pancost, M.R., Patnaik, A., Shao, W., Shultz, M., Tichkule, R., Tommasi, R.A., Vash, B., Wang, P., and Stams, T. (2011). Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors. Bioorg. Med. Chem. 19: 4626–4634.
- 107Aramsangtienchai, P., Spiegelman, N.A., He, B., Miller, S.P., Dai, L., Zhao, Y., and Lin, H. (2016). HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine. ACS Chem. Biol. 11: 2685–2692.
- 108Zhao, C., Zhang, J., Zhou, H., Setroikromo, R., Poelarends, G.J., and Dekker, F.J. (2024). Exploration of hydrazide-based HDAC8 PROTACs for the treatment of hematological malignancies and solid tumors. J. Med. Chem. 67: 14016–14039.
- 109Mielcarek, M., Zielonka, D., Carnemolla, A., Marcinkowski, J.T., and Guidez, F. (2015). HDAC4 as a potential therapeutic target in neurodegenerative diseases: A summary of recent achievements. Front. Cell. Neurosci. 9: 42.
- 110Shukla, S. and Tekwani, B.L. (2020). Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation. Front. Pharmacol. 11: 537.
- 111Ziemka-Nalecz, M., Jaworska, J., Sypecka, J., and Zalewska, T. (2018). Histone deacetylase inhibitors: A therapeutic key in neurological disorders? J. Neuropathol. Exp. Neurol. 77: 855–870.
- 112Lobera, M., Madauss, K.P., Pohlhaus, D.T., Wright, Q.G., Trocha, M., Schmidt, D.R., Baloglu, E., Trump, R.P., Head, M.S., Hofmann, G.A., Murray-Thompson, M., Schwartz, B., Chakravorty, S., Wu, Z., Mander, P.K., Kruidenier, L., Reid, R.A., Burkhart, W., Turunen, B.J., Rong, J.X., Wagner, C., Moyer, M.B., Wells, C., Hong, X., Moore, J.T., Williams, J.D., Soler, D., Ghosh, S., and Nolan, M.A. (2013). Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat. Chem. Biol. 9: 319–325.
- 113Macabuag, N., Esmieu, W., Breccia, P., Jarvis, R., Blackaby, W., Lazari, O., Urbonas, L., Eznarriaga, M., Williams, R., Strijbosch, A., Van De Bospoort, R., Matthews, K., Clissold, C., Ladduwahetty, T., Vater, H., Heaphy, P., Stafford, D.G., Wang, H.-J., Mangette, J.E., Mcallister, G., Beaumont, V., Vogt, T.F., Wilkinson, H.A., Doherty, E.M., and Dominguez, C. (2022). Developing HDAC4-selective protein degraders to investigate the role of HDAC4 in Huntington's disease pathology. J. Med. Chem. 65: 12445–12459.
- 114Xiong, Y., Donovan, K.A., Eleuteri, N.A., Kirmani, N., Yue, H., Razov, A., Krupnick, N.M., Nowak, R.P., and Fischer, E.S. (2021). Chemo-proteomics exploration of HDAC degradability by small molecule degraders. Cell Chem. Biol. 28: 1514–1527.e4.
- 115Donovan, K.A., Ferguson, F.M., Bushman, J.W., Eleuteri, N.A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X., Dobrovolsky, D., Jiang, B., Wang, J., Hao, M., You, I., Teng, M., Liang, Y., Hatcher, J., Li, Z., Manz, T.D., Groendyke, B., Hu, W., Nam, Y., Sengupta, S., Cho, H., Shin, I., Agius, M.P., Ghobrial, I.M., Ma, M.W., Che, J., Buhrlage, S.J., Sim, T., Gray, N.S., and Fischer, E.S. (2020). Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183: 1714–1731.e10.
- 116Sievers, Q.L., Petzold, G., Bunker, R.D., Renneville, A., Słabicki, M., Liddicoat, B.J., Abdulrahman, W., Mikkelsen, T., Ebert, B.L., and Thomä, N.H. (2018). Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362: eaat0572.
- 117Martin, C. and Zhang, Y. (2005). The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6: 838–849.
- 118Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A., and Shi, Y. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119: 941–953.
- 119Ponnaluri, V.K.C., Vavilala, D.T., Putty, S., Gutheil, W.G., and Mukherji, M. (2009). Identification of non-histone substrates for JMJD2A–C histone demethylases. Biochem. Biophys. Res. Commun. 390: 280–284.
- 120Walport, L.J., Hopkinson, R.J., Chowdhury, R., Schiller, R., Ge, W., Kawamura, A., and Schofield, C.J. (2016). Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases. Nat. Commun. 7: 11974.
- 121Hamamoto, R., Saloura, V., and Nakamura, Y. (2015). Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat. Rev. Cancer 15: 110–124.
- 122Kaniskan, H.Ü., Martini, M.L., and Jin, J. (2018). Inhibitors of protein methyltransferases and demethylases. Chem. Rev. 118: 989–1068.
- 123Markolovic, S., Leissing, T.M., Chowdhury, R., Wilkins, S.E., Lu, X., and Schofield, C.J. (2016). Structure–function relationships of human JmjC oxygenases—demethylases versus hydroxylases. Curr. Opin. Struct. Biol. 41: 62–72.
- 124Zhang, L., Chen, Y., Li, Z., Lin, C., Zhang, T., and Wang, G. (2023). Development of JmjC-domain-containing histone demethylase (KDM2-7) inhibitors for cancer therapy. Drug Discov. Today 28: 103519.
- 125Arifuzzaman, S., Khatun, M.R., and Khatun, R. (2020). Emerging of lysine demethylases (KDMs): From pathophysiological insights to novel therapeutic opportunities. Biomed. Pharmacother. 129: 110392.
- 126Yang, G.-J., Zhu, M.-H., Lu, X.-J., Liu, Y.-J., Lu, J.-F., Leung, C.-H., Ma, D.-L., and Chen, J. (2021). The emerging role of KDM5A in human cancer. J. Hematol. Oncol. 14: 30.
- 127Pavlenko, E., Ruengeler, T., Engel, P., and Poepsel, S. (2022). Functions and interactions of mammalian KDM5 demethylases. Front. Genet. 13: 906662.
- 128Iida, T., Itoh, Y., Takahashi, Y., Yamashita, Y., Kurohara, T., Miyake, Y., Oba, M., and Suzuki, T. (2021). Design, synthesis, and niological evaluation of lysine demethylase 5 C degraders. ChemMedChem 16: 1609–1618.
- 129Meanwell, N.A. (2023). Applications of bioisosteres in the design of biologically active compounds. J. Agric. Food Chem. 71: 18087–18122.
- 130Miyake, Y., Itoh, Y., Suzuma, Y., Kodama, H., Kurohara, T., Yamashita, Y., Narozny, R., Hanatani, Y., Uchida, S., and Suzuki, T. (2020). Metalloprotein-catalyzed click reaction for in situ generation of a potent inhibitor. ACS Catal. 10: 5383–5392.
- 131Guan, T., Zhang, Y., Li, S., Zhang, W., Song, Y., Li, Y., He, Y., and Chen, Y. (2024). Discovery of an efficacious KDM5B PROTAC degrader GT-653 up-regulating IFN response genes in prostate cancer. Eur. J. Med. Chem. 272: 116494.
- 132Vinogradova, M., Gehling, V.S., Gustafson, A., Arora, S., Tindell, C.A., Wilson, C., Williamson, K.E., Guler, G.D., Gangurde, P., Manieri, W., Busby, J., Flynn, E.M., Lan, F., Kim, H.-J., Odate, S., Cochran, A.G., Liu, Y., Wongchenko, M., Yang, Y., Cheung, T.K., Maile, T.M., Lau, T., Costa, M., Hegde, G.V., Jackson, E., Pitti, R., Arnott, D., Bailey, C., Bellon, S., Cummings, R.T., Albrecht, B.K., Harmange, J.-C., Kiefer, J.R., Trojer, P., and Classon, M. (2016). An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 12: 531–538.
- 133Iida, T., Itoh, Y., Takahashi, Y., Miyake, Y., Zamani, F., Yamashita, Y., Takada, Y., Akiyama, T., Ibaraki, J., Okuda, K., Tokuda, Y., Nishimura, T., Hidaka, K., Mori, H., Oba, M., and Suzuki, T. (2024). Identification of proteolysis targeting chimeras (PROTACs) for lysine demethylase 5 and their neurite outgrowth-promoting activity. Chem. Pharm. Bull. 72: 638–647.
- 134Zaman, S.U., Pagare, P.P., Ma, H., Hoyle, R.G., Zhang, Y., and Li, J. (2024). Novel PROTAC probes targeting KDM3 degradation to eliminate colorectal cancer stem cells through inhibition of Wnt/β-catenin signaling. RSC Med. Chem. 15: 3746–3758.
- 135Esbaugh, A.J. and Tufts, B.L. (2006). The structure and function of carbonic anhydrase isozymes in the respiratory system of vertebrates. Respir. Physiol. Neurobiol. 154: 185–198.
- 136Occhipinti, R. and Boron, W.F. (2019). Role of carbonic anhydrases and inhibitors in acid–base physiology: Insights from mathematical modeling. Int. J. Mol. Sci. 20: 3841–3871.
- 137Al-Samir, S., Papadopoulos, S., Scheibe, R.J., Meißner, J.D., Cartron, J.P., Sly, W.S., Alper, S.L., Gros, G., and Endeward, V. (2013). Activity and distribution of intracellular carbonic anhydrase II and their effects on the transport activity of anion exchanger AE1/SLC4A1. J. Physiol. 591: 4963–4982.
- 138Imtaiyaz Hassan, M., Shajee, B., Waheed, A., Ahmad, F., and Sly, W.S. (2013). Structure, function and applications of carbonic anhydrase isozymes. Bioorg. Med. Chem. 21: 1570–1582.
- 139Nocentini, A., Donald, W.A., and Supuran, C.T. (2019). Chapter 8 – Human carbonic anhydrases: Tissue distribution, physiological role, and druggability. In: Carbonic Anhydrases (ed. C.T. Supuran and A. Nocentini). Academic Press.
10.1016/B978-0-12-816476-1.00008-3 Google Scholar
- 140Krishnamurthy, V.M., Kaufman, G.K., Urbach, A.R., Gitlin, I., Gudiksen, K.L., Weibel, D.B., and Whitesides, G.M. (2008). Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein−ligand binding. Chem. Rev. 108: 946–1051.
- 141Aggarwal, M., Boone, C.D., Kondeti, B., and Mckenna, R. (2013). Structural annotation of human carbonic anhydrases. J. Enzyme Inhib. Med. Chem. 28: 267–277.
- 142Supuran, C.T. (2016). Structure and function of carbonic anhydrases. Biochem. J. 473: 2023–2032.
- 143Mishra, C.B., Tiwari, M., and Supuran, C.T. (2020). Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today? Med. Res. Rev. 40: 2485–2565.
- 144Sippel, K.H., Robbins, A.H., Domsic, J., Genis, C., Agbandje-Mckenna, M., and Mckenna, R. (2009). High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. Acta Crystallogr. 65: 992–995.
- 145Zamanova, S., Shabana, A.M., Mondal, U.K., and Ilies, M.A. (2019). Carbonic anhydrases as disease markers. Expert Opin. Ther. Pat. 29: 509–533.
- 146Kumar, A., Siwach, K., Supuran, C.T., and Sharma, P.K. (2022). A decade of tail-approach based design of selective as well as potent tumor associated carbonic anhydrase inhibitors. Bioorg. Chem. 126: 105920.
- 147Kumar, S., Rulhania, S., Jaswal, S., and Monga, V. (2021). Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors. Eur. J. Med. Chem. 209: 112923.
- 148Noor, S.I., Jamali, S., Ames, S., Langer, S., Deitmer, J.W., and Becker, H.M. (2018). A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells. elife 7: e35176.
- 149Supuran, C.T., Capasso, C., and De Simone, G. (2015). Chapter 4 – Carbonic anhydrase II as target for drug design. In: Carbonic Anhydrases as Biocatalysts (ed. C.T. Supuran and G. Simone). Amsterdam: Elsevier.
10.1016/B978-0-444-63258-6.00004-4 Google Scholar
- 150O'Herin, C.B., Moriuchi, Y.W., Bemis, T.A., Kohlbrand, A.J., Burkart, M.D., and Cohen, S.M. (2023). Development of human carbonic anhydrase II heterobifunctional degraders. J. Med. Chem. 66: 2789–2803.
- 151Munn, D.H., Zhou, M., Attwood, J.T., Bondarev, I., Conway, S.J., Marshall, B., Brown, C., and Mellor, A.L. (1998). Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281: 1191–1193.
- 152Seo, S.-K. and Kwon, B. (2023). Immune regulation through tryptophan metabolism. Exp. Mol. Med. 55: 1371–1379.
- 153Liu, M., Wang, X., Wang, L., Ma, X., Gong, Z., Zhang, S., and Li, Y. (2018). Targeting the IDO1 pathway in cancer: From bench to bedside. J. Hematol. Oncol. 11: 100.
- 154Lewis-Ballester, A., Pham, K.N., Batabyal, D., Karkashon, S., Bonanno, J.B., Poulos, T.L., and Yeh, S.-R. (2017). Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nat. Commun. 8: 1693.
- 155Röhrig, U.F., Michielin, O., and Zoete, V. (2021). Structure and plasticity of indoleamine 2,3-dioxygenase 1 (IDO1). J. Med. Chem. 64: 17690–17705.
- 156Tang, K., Wu, Y.-H., Song, Y., and Yu, B. (2021). Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J. Hematol. Oncol. 14: 68.
- 157Feng, X., Liao, D., Liu, D., Ping, A., Li, Z., and Bian, J. (2020). Development of indoleamine 2,3-dioxygenase 1 inhibitors for cancer therapy and beyond: A recent perspective. J. Med. Chem. 63: 15115–15139.
- 158Hu, M., Zhou, W., Wang, Y., Yao, D., Ye, T., Yao, Y., Chen, B., Liu, G., Yang, X., Wang, W., and Xie, Y. (2020). Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1. Acta Pharm. Sin. B 10: 1943–1953.
- 159Bollu, L.R., Bommi, P.V., Monsen, P.J., Zhai, L., Lauing, K.L., Bell, A., Kim, M., Ladomersky, E., Yang, X., Platanias, L.C., Matei, D.E., Bonini, M.G., Munshi, H.G., Hashizume, R., Wu, J.D., Zhang, B., James, C.D., Chen, P., Kocherginsky, M., Horbinski, C., Cameron, M.D., Grigorescu, A.A., Yamini, B., Lukas, R.V., Schiltz, G.E., and Wainwright, D.A. (2022). Identification and characterization of a novel indoleamine 2,3-dioxygenase 1 protein degrader for glioblastoma. J. Med. Chem. 65: 15642–15662.
- 160Dong, G., Ding, Y., He, S., and Sheng, C. (2021). Molecular glues for targeted protein degradation: From serendipity to rational discovery. J. Med. Chem. 64: 10606–10620.
- 161Dewey, J.A., Delalande, C., Azizi, S.-A., Lu, V., Antonopoulos, D., and Babnigg, G. (2023). Molecular glue discovery: Current and future approaches. J. Med. Chem. 66: 9278–9296.
- 162Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., and Mayor-Ruiz, C. (2022). Chasing molecular glue degraders: Screening approaches. Chem. Soc. Rev. 51: 5498–5517.
- 163Holdgate, G.A., Bardelle, C., Berry, S.K., Lanne, A., and Cuomo, M.E. (2024). Screening for molecular glues – Challenges and opportunities. SLAS Discov. 29: 100136.
- 164Robinson, S.A., Co, J.A., and Banik, S.M. (2024). Molecular glues and induced proximity: An evolution of tools and discovery. Cell Chem. Biol. 31: 1089–1100.
- 165Toriki, E.S., Papatzimas, J.W., Nishikawa, K., Dovala, D., Frank, A.O., Hesse, M.J., Dankova, D., Song, J.-G., Bruce-Smythe, M., Struble, H., Garcia, F.J., Brittain, S.M., Kile, A.C., Mcgregor, L.M., Mckenna, J.M., Tallarico, J.A., Schirle, M., and Nomura, D.K. (2023). Rational chemical design of molecular glue degraders. ACS Central Sci. 9: 915–926.
- 166Bashore, C., Prakash, S., Johnson, M.C., Conrad, R.J., Kekessie, I.A., Scales, S.J., Ishisoko, N., Kleinheinz, T., Liu, P.S., Popovych, N., Wecksler, A.T., Zhou, L., Tam, C., Zilberleyb, I., Srinivasan, R., Blake, R.A., Song, A., Staben, S.T., Zhang, Y., Arnott, D., Fairbrother, W.J., Foster, S.A., Wertz, I.E., Ciferri, C., and Dueber, E.C. (2023). Targeted degradation via direct 26S proteasome recruitment. Nat. Chem. Biol. 19: 55–63.
- 167Verma, R., Aravind, L., Oania, R., Mcdonald, W.H., Yates, J.R., Koonin, E.V., and Deshaies, R.J. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S Proteasome. Science 298: 611–615.
- 168Kim, J., Byun, I., Kim, D.Y., Joh, H., Kim, H.J., and Lee, M.J. (2024). Targeted protein degradation directly engaging lysosomes or proteasomes. Chem. Soc. Rev. 53: 3253–3272.
- 169Paudel, R.R., Lu, D., Roy Chowdhury, S., Monroy, E.Y., and Wang, J. (2023). Targeted protein degradation via lysosomes. Biochemistry 62: 564–579.
- 170Raina, K., Forbes, C.D., Stronk, R., Rappi, J.P. Jr., Eastman, K.J., Zaware, N., Yu, X., Li, H., Bhardwaj, A., Gerritz, S.W., Forgione, M., Hundt, A., King, M.P., Posner, Z.M., Correia, A.D., Mcgovern, A., Puleo, D.E., Chenard, R., Mousseau, J.J., Vergara, J.I., Garvin, E., Macaluso, J., Martin, M., Bassoli, K., Jones, K., Garcia, M., Howard, K., Yaggi, M., Smith, L.M., Chen, J.M., Mayfield, A.B., De Leon, C.A., Hines, J., Kayser-Bricker, K.J., and Crews, C.M. (2024). Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies. Cell Chem. Biol. 31: 1490–1502.e42.
- 171Ji, C.H., Lee, M.J., Kim, H.Y., Heo, A.J., Park, D.Y., Kim, Y.K., Kim, B.Y., and Kwon, Y.T. (2022). Targeted protein degradation via the autophagy-lysosome system: AUTOTAC (AUTOphagy-TArgeting Chimera). Autophagy 18: 2259–2262.
- 172Banik, S.M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N.M., and Bertozzi, C.R. (2020). Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584: 291–297.
- 173Zheng, J., He, W., Li, J., Feng, X., Li, Y., Cheng, B., Zhou, Y., Li, M., Liu, K., Shao, X., Zhang, J., Li, H., Chen, L., and Fang, L. (2022). Bifunctional compounds as molecular degraders for integrin-facilitated targeted protein degradation. J. Am. Chem. Soc. 144: 21831–21836.
- 174Zhu, C., Wang, W., Wang, Y., Zhang, Y., and Li, J. (2023). Dendronized DNA chimeras harness scavenger receptors to degrade cell membrane proteins. Angew. Chem. Int. Ed. 62: e202300694.
- 175Pance, K., Gramespacher, J.A., Byrnes, J.R., Salangsang, F., Serrano, J.-A.C., Cotton, A.D., Steri, V., and Wells, J.A. (2023). Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat. Biotechnol. 41: 273–281.
- 176Zhu, C., Wang, W., Wang, Y., Zhang, W., Zhang, Y., and Li, J. (2024). Targeted extracellular protein degradation by dendronized DNA chimeras. ACS Chem. Biol. 19: 654–659.
- 177Liu, X. and Ciulli, A. (2023). Proximity-based modalities for biology and medicine. ACS Central Sci. 9: 1269–1284.
- 178Konstantinidou, M. and Arkin, M.R. (2024). Molecular glues for protein–protein interactions: Progressing toward a new dream. Cell Chem. Biol. 31: 1064–1088.
- 179Siriwardena, S.U., Munkanatta Godage, D.N.P., Shoba, V.M., Lai, S., Shi, M., Wu, P., Chaudhary, S.K., Schreiber, S.L., and Choudhary, A. (2020). Phosphorylation-inducing chimeric small molecules. J. Am. Chem. Soc. 142: 14052–14057.
- 180Zhang, Q., Wu, X., Zhang, H., Wu, Q., Fu, M., Hua, L., Zhu, X., Guo, Y., Zhang, L., You, Q., and Wang, L. (2023). Protein phosphatase 5-recruiting chimeras for accelerating apoptosis-signal-regulated kinase 1 dephosphorylation with antiproliferative activity. J. Am. Chem. Soc. 145: 1118–1128.
- 181Henning, N.J., Boike, L., Spradlin, J.N., Ward, C.C., Liu, G., Zhang, E., Belcher, B.P., Brittain, S.M., Hesse, M.J., Dovala, D., Mcgregor, L.M., Valdez Misiolek, R., Plasschaert, L.W., Rowlands, D.J., Wang, F., Frank, A.O., Fuller, D., Estes, A.R., Randal, K.L., Panidapu, A., Mckenna, J.M., Tallarico, J.A., Schirle, M., and Nomura, D.K. (2022). Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 18: 412–421.
