4QVX

Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo

Summary for 4QVX

• Entry DOI: 10.2210/pdb4qvx/pdb
• Related: 4TUH
• Descriptor: Bcl-2-like protein 1, 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-5-(3-{4-[3-(dimethylamino)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid (3 entities in total)
• Functional Keywords: 8 alpha helices, anti-apoptotic, pro-apoptotic, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817
• Total number of polymer chains: 2
• Total formula weight: 38719.21

Authors

Park, C.H. (deposition date: 2014-07-16, release date: 2015-07-22, Last modification date: 2024-02-28)

Primary citation

Tao, Z.F.,Hasvold, L.,Wang, L.,Wang, X.,Petros, A.M.,Park, C.H.,Boghaert, E.R.,Catron, N.D.,Chen, J.,Colman, P.M.,Czabotar, P.E.,Deshayes, K.,Fairbrother, W.J.,Flygare, J.A.,Hymowitz, S.G.,Jin, S.,Judge, R.A.,Koehler, M.F.,Kovar, P.J.,Lessene, G.,Mitten, M.J.,Ndubaku, C.O.,Nimmer, P.,Purkey, H.E.,Oleksijew, A.,Phillips, D.C.,Sleebs, B.E.,Smith, B.J.,Smith, M.L.,Tahir, S.K.,Watson, K.G.,Xiao, Y.,Xue, J.,Zhang, H.,Zobel, K.,Rosenberg, S.H.,Tse, C.,Leverson, J.D.,Elmore, S.W.,Souers, A.J.
Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
ACS MED.CHEM.LETT., 5:1088-1093, 2014

PubMed Abstract: A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

PubMed: 25313317
DOI: 10.1021/ml5001867

Experimental method

X-RAY DIFFRACTION (2.1 Å)