6VWC

Crystal structure of Bcl-xL in complex with tetrahydroisoquinoline-pyridine based inhibitors

Summary for 6VWC

• Entry DOI: 10.2210/pdb6vwc/pdb
• Descriptor: Bcl-2-like protein 1, 6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}-3-{1-[(pyridin-4-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic acid (3 entities in total)
• Functional Keywords: bcl-xl inhibitor, apoptosis, structure-based drug design, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 38554.93

Authors

Judge, R.A.,Judd, A.S. (deposition date: 2020-02-19, release date: 2020-10-21, Last modification date: 2023-10-11)

Primary citation

Wang, L.,Doherty, G.A.,Judd, A.S.,Tao, Z.F.,Hansen, T.M.,Frey, R.R.,Song, X.,Bruncko, M.,Kunzer, A.R.,Wang, X.,Wendt, M.D.,Flygare, J.A.,Catron, N.D.,Judge, R.A.,Park, C.H.,Shekhar, S.,Phillips, D.C.,Nimmer, P.,Smith, M.L.,Tahir, S.K.,Xiao, Y.,Xue, J.,Zhang, H.,Le, P.N.,Mitten, M.J.,Boghaert, E.R.,Gao, W.,Kovar, P.,Choo, E.F.,Diaz, D.,Fairbrother, W.J.,Elmore, S.W.,Sampath, D.,Leverson, J.D.,Souers, A.J.
Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X L Inhibitor.
Acs Med.Chem.Lett., 11:1829-1836, 2020

PubMed Abstract: Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X inhibitor that selectively and potently induces apoptosis in BCL-X-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.

PubMed: 33062160
DOI: 10.1021/acsmedchemlett.9b00568

Experimental method

X-RAY DIFFRACTION (1.604 Å)