Design and Synthesis of Novel 3-(2-Aminopyridin-3-yl)-1,2,4-Triazolo[4,3-b]Pyridazine Derivatives as a Reversible Bruton's Tyrosine Kinase Inhibitors
Corresponding Author
Chi Hoon Park
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorDukwoon Kim
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorHyeonseok Jung
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorJeong Hee Jeon
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorRaghavendra Achary
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorJoo-Youn Lee
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorPilho Kim
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorHeejung Jung
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorJong Yeon Hwang
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorDo Hyun Ryu
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorJae Du Ha
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorCorresponding Author
Sung Yun Cho
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorCorresponding Author
Chi Hoon Park
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorDukwoon Kim
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorHyeonseok Jung
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorJeong Hee Jeon
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorRaghavendra Achary
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorJoo-Youn Lee
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorPilho Kim
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorHeejung Jung
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorJong Yeon Hwang
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 305-550 South Korea
Search for more papers by this authorDo Hyun Ryu
Department of Chemistry, Sungkyunkwan University, Suwon, 440-746 South Korea
Search for more papers by this authorJae Du Ha
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorCorresponding Author
Sung Yun Cho
Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606 South Korea
Search for more papers by this authorAbstract
Bruton's tyrosine kinase, a non-receptor TEC family kinase, plays key role in B cell differentiation, proliferation, and survival. B cell receptor regulates the B cell's fate and cytokine release of B-lineage lymphoid leukemia cells which are deeply related with the pathogenesis of B-cell lineage of lymphoma and leukemia and autoimmune diseases. Thus, BTK protein regulation emerged as a promising therapeutic target for both various cancers and autoimmune diseases. Herein, we report the discovery of aminopyridin-1,2,4-triazolopyridazine derivatives as a reversible BTK inhibitor, and in vitro enzyme assay and cell based assay result were reported.
Supporting Information
| Filename | Description |
|---|---|
| bkcs11485-sup-0001-AppendixS1.docxWord 2007 document , 70.2 KB |
Table S1. Results of BTK inhibition and cell proliferation assays in the TMD8 cell line. Table S2. Ambit assay. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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- 7Bioassays. Enzyme and cell-based assay. Enzyme assay. The experimental procedure was performed following the manufacturer's instructions (Cisbio, Codolet, France). The reaction was initiated by the addition of ATP to a mixture containing BTK, peptide substrates, and inhibitors. After 30 min, an EDTA-containing solution was added to stop the reaction. The EDTA containing solution included Europium-conjugated antiphospho residue antibody and streptavidine-XL665 (SA-XL665; Cisbio, France) for the detection of the phosphorylated peptide product. After 1 h of incubation, fluorescence was measured using an Envision reader at 337 nm excitation and dual 665 and 620 nm emissions. The half maximal inhibitory concentration (IC50) was calculated using GraphPad Prism version 5 for Windows (La Jolla, CA, USA). The curves were fitted using a nonlinear regression model with a log (inhibitor) vs. response formula. Cell-based assay. For viability experiments, TMD-8 cells were seeded in 96-well plates at 30% confluency and exposed to chemicals. After 72 h, WST-1 reagent was added, and absorbance was measured at 450 nm using a Spectramax spectrophotometer (Molecular Devices, Sunnyvale, CA, USA) according to the manufacturer's instructions. The IC50 values were calculated using GraphPad Prism version 5 for Windows. The curves were fitted using a nonlinear regression model with a log (inhibitor) vs. response formula.
- 8Molecular modeling study of 13b against the BTK was performed using the Schrödinger Suite 2017–4 (Schrödinger, LLC, Cambridge, MA, USA; http://www.schrodinger.com). The X-ray crystal structure obtained from the Protein Data Bank (http://www.rcsb.org) that PDB code is 4YHF. The protein preparation was revised using Protein Preparation Wizard in Maestro v.11.4 and the receptor grid box was generated 25 x 25 x 25 Å cubic size centered on complexed ligand. The 13b was minimized using an OPLS_2005 force field with a dielectric constant value 80.0 in MacroModel v11.8. Flexible ligand docking was performed using the Glide v.7.7 with standard precision method. The binding model of ligand was visualized using Discovery Studio 2017 (Biovia, San Diego, CA, USA; http://www.accelrys.com).
- 9https://www.rcsb.org/structure/4YHF
