3SPF

Crystal Structure of Bcl-xL bound to BM501

Summary for 3SPF

• Entry DOI: 10.2210/pdb3spf/pdb
• Related: 3SP7
• Descriptor: Bcl-2-like protein 1, 4-(4-chlorophenyl)-1-[(3S)-3,4-dihydroxybutyl]-N-[3-(4-methylpiperazin-1-yl)propyl]-3-phenyl-1H-pyrrole-2-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: bcl-2-like protein, apoptosis-apoptosis inhibitor complex, apoptosis regulator-inhibitor complex, apoptosis regulator/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817
• Total number of polymer chains: 1
• Total formula weight: 20570.04

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2011-07-01, release date: 2012-06-27, Last modification date: 2024-02-28)

Primary citation

Zhou, H.,Chen, J.,Meagher, J.L.,Yang, C.Y.,Aguilar, A.,Liu, L.,Bai, L.,Cong, X.,Cai, Q.,Fang, X.,Stuckey, J.A.,Wang, S.
Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold.
J.Med.Chem., 55:4664-4682, 2012

PubMed Abstract: Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM.

PubMed: 22448988
DOI: 10.1021/jm300178u

Experimental method

X-RAY DIFFRACTION (1.7 Å)