Structure-Guided Discovery of a Potent and Selective Cell-Active Inhibitor of SETDB1 Tudor Domain
Yinping Guo
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorXin Mao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorLiang Xiong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorAnjie Xia
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorJing You
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorGuifeng Lin
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorChengyong Wu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorLuyi Huang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorYiwei Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Dr. Shengyong Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorYinping Guo
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorXin Mao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorLiang Xiong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorAnjie Xia
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorJing You
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorGuifeng Lin
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorChengyong Wu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorLuyi Huang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorYiwei Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorCorresponding Author
Prof. Dr. Shengyong Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041 P. R. China
Search for more papers by this authorGraphical Abstract
The first potent and selective small-molecule SETDB1 tandem tudor domain (TTD) inhibitor, (R,R)-59, is reported. (R,R)-59 is an endogenous binder-competitive inhibitor and also showed activities in intact cells. The enantiomer (S,S)-59 did not show any activity.
Abstract
SET domain bifurcated protein 1 (SETDB1) is a histone lysine methyltransferase that promotes the silencing of some tumour suppressor genes and is overexpressed in many cancers. SETDB1 contains a unique tandem tudor domain (TTD) that recognizes histone H3 sequences containing both methylated and acetylated lysines. Beginning with the identification of a hit compound (Cpd1), we discovered the first potent and selective small molecule SETDB1-TTD inhibitor (R,R)-59 through stepwise structure-guided optimization. (R,R)-59 showed a KD value of 0.088±0.045 μM in the ITC assay. The high potency of (R,R)-59 was well explained by the cocrystal structure of the (R,R)-59-TTD complex. (R,R)-59 is an endogenous binder competitive inhibitor. Evidence has also demonstrated its cellular target engagement. Interestingly, the enantiomer (S,S)-59 did not show activity in all the assays, highlighting the potential of (R,R)-59 as a tool compound in exploring the biological functions of SETDB1-TTD.
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References
- 1
- 1aB. D. Strahl, C. D. Allis, Nature 2000, 403, 41–45;
- 1bC. A. Musselman, M. E. Lalonde, J. Cote, T. G. Kutateladze, Nat. Struct. Mol. Biol. 2012, 19, 1218–1227.
- 2
- 2aM. A. Dawson, Science 2017, 355, 1147–1152;
- 2bF. P. Vendetti, C. M. Rudin, Expert Opin. Biol. Ther. 2013, 13, 1273–1285.
- 3
- 3aP. Filippakopoulos, S. Knapp, Nat. Rev. Drug Discovery 2014, 13, 337–356;
- 3bM. A. Dawson, T. Kouzarides, B. J. Huntly, N. Engl. J. Med. 2012, 367, 647–657.
- 4
- 4aN. Zaware, M. M. Zhou, Curr. Opin. Chem. Biol. 2017, 39, 116–125;
- 4bC. H. Arrowsmith, M. Schapira, Nat. Struct. Mol. Biol. 2019, 26, 863–869.
- 5
- 5aR. Lu, G. G. Wang, Trends Biochem. Sci. 2013, 38, 546–555;
- 5bZ. Ren, J. H. Ahn, H. Liu, Y. H. Tsai, N. V. Bhanu, B. Koss, D. F. Allison, A. Ma, A. J. Storey, P. Wang, S. G. Mackintosh, R. D. Edmondson, R. W. J. Groen, A. C. Martens, B. A. Garcia, A. J. Tackett, J. Jin, L. Cai, D. Zheng, G. G. Wang, Blood 2019, 134, 1176–1189.
- 6
- 6aY. Duan, Y. Guan, W. Qin, X. Zhai, B. Yu, H. Liu, MedChemComm 2018, 9, 1779–1802;
- 6bG. S. Sheppard, L. Wang, S. D. Fidanze, L. A. Hasvold, D. Liu, J. K. Pratt, C. H. Park, K. Longenecker, W. Qiu, M. Torrent, P. J. Kovar, M. Bui, E. Faivre, X. Huang, X. Lin, D. Wilcox, L. Zhang, Y. Shen, D. H. Albert, T. J. Magoc, G. Rajaraman, W. M. Kati, K. F. McDaniel, J. Med. Chem. 2020, 63, 5585–5623;
- 6cA. G. Cochran, A. R. Conery, R. J. Sims 3rd, Nat. Rev. Drug Discovery 2019, 18, 609–628.
- 7
- 7aN. Bae, M. Viviano, X. Su, J. Lv, D. Cheng, C. Sagum, S. Castellano, X. Bai, C. Johnson, M. I. Khalil, J. Shen, K. Chen, H. Li, G. Sbardella, M. T. Bedford, Nat. Chem. Biol. 2017, 13, 750–756;
- 7bY. Xiong, H. Greschik, C. Johansson, L. Seifert, J. Bacher, K. S. Park, N. Babault, M. Martini, V. Fagan, F. Li, I. Chau, T. Christott, D. Dilworth, D. Barsyte-Lovejoy, M. Vedadi, C. H. Arrowsmith, P. Brennan, O. Fedorov, M. Jung, G. Farnie, J. Liu, U. Oppermann, R. Schule, J. Jin, J. Med. Chem. 2019, 62, 8996–9007;
- 7cV. Fagan, C. Johansson, C. Gileadi, O. Monteiro, J. E. Dunford, R. Nibhani, M. Philpott, J. Malzahn, G. Wells, R. Faram, A. P. Cribbs, N. Halidi, F. Li, I. Chau, H. Greschik, S. Velupillai, A. Allali-Hassani, J. Bennett, T. Christott, C. Giroud, A. M. Lewis, K. V. M. Huber, N. Athanasou, C. Bountra, M. Jung, R. Schule, M. Vedadi, C. Arrowsmith, Y. Xiong, J. Jin, O. Fedorov, G. Farnie, P. E. Brennan, U. Oppermann, J. Med. Chem. 2019, 62, 9008–9025;
- 7dG. Senisterra, H. Y. Zhu, X. Luo, H. Zhang, G. Xun, C. Lu, W. Xiao, T. Hajian, P. Loppnau, I. Chau, F. Li, A. Allali-Hassani, P. Atadja, C. Oyang, E. Li, P. J. Brown, C. H. Arrowsmith, K. Zhao, Z. Yu, M. Vedadi, SLAS Discovery 2018, 23, 930–940;
- 7eM. T. Perfetti, B. M. Baughman, B. M. Dickson, Y. Mu, G. Cui, P. Mader, A. Dong, J. L. Norris, S. B. Rothbart, B. D. Strahl, P. J. Brown, W. P. Janzen, C. H. Arrowsmith, G. Mer, K. M. McBride, L. I. James, S. V. Frye, ACS Chem. Biol. 2015, 10, 1072–1081.
- 8
- 8aE. Orouji, A. Federico, L. Larribere, D. Novak, D. B. Lipka, Y. Assenov, S. Sachindra, L. Huser, K. Granados, C. Gebhardt, C. Plass, V. Umansky, J. Utikal, Int. J. Cancer 2019, 145, 3462–3477;
- 8bQ. Fei, K. Shang, J. Zhang, S. Chuai, D. Kong, T. Zhou, S. Fu, Y. Liang, C. Li, Z. Chen, Y. Zhao, Z. Yu, Z. Huang, M. Hu, H. Ying, Z. Chen, Y. Zhang, F. Xing, J. Zhu, H. Xu, K. Zhao, C. Lu, P. Atadja, Z. X. Xiao, E. Li, J. Shou, Nat. Commun. 2015, 6, 8651.
- 9Y. K. Kang, Curr. Issues Mol. Biol. 2015, 17, 1–10.
- 10J. W. Pek, A. Anand, T. Kai, Development 2012, 139, 2255–2266.
- 11R. Z. Jurkowska, S. Qin, G. Kungulovski, W. Tempel, Y. Liu, P. Bashtrykov, J. Stiefelmaier, T. P. Jurkowski, S. Kudithipudi, S. Weirich, R. Tamas, H. Wu, L. Dombrovski, P. Loppnau, R. Reinhardt, J. Min, A. Jeltsch, Nat. Commun. 2017, 8, 2057.
- 12P. Mader, R. Mendoza-Sanchez, A. Iqbal, A. Dong, E. Dobrovetsky, V. B. Corless, S. K. Liew, S. R. Houliston, R. F. De Freitas, D. Smil, C. C. D. Sena, S. Kennedy, D. B. Diaz, H. Wu, L. Dombrovski, A. Allali-Hassani, J. Min, M. Schapira, M. Vedadi, P. J. Brown, V. Santhakumar, A. K. Yudin, C. H. Arrowsmith, Bioorg. Med. Chem. 2019, 27, 3866–3878.
