7N5O

Fragment-Based Discovery of a Novel Bruton's Tyrosine Kinase Inhibitor

Summary for 7N5O

• Entry DOI: 10.2210/pdb7n5o/pdb
• Descriptor: Tyrosine-protein kinase BTK, IMIDAZOLE, S-1,2-PROPANEDIOL, ... (6 entities in total)
• Functional Keywords: cytoplasmic tyrosine kinase, transcriptional regulation, nuclear factor-kappab, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33098.94

Authors

Dougan, D.R.,Lawson, J.D. (deposition date: 2021-06-06, release date: 2021-09-08, Last modification date: 2023-10-18)

Primary citation

Sabat, M.,Dougan, D.R.,Knight, B.,Lawson, J.D.,Scorah, N.,Smith, C.R.,Taylor, E.R.,Vu, P.,Wyrick, C.,Wang, H.,Balakrishna, D.,Hixon, M.,Madakamutil, L.,McConn, D.
Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 ( S )-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3 H -1,2,4-triazol-3-one, by Fragment-Based Drug Design.
J.Med.Chem., 64:12893-12902, 2021

PubMed Abstract: This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.

PubMed: 34448571
DOI: 10.1021/acs.jmedchem.1c01026

Experimental method

X-RAY DIFFRACTION (1.25 Å)