4LVT

Bcl_2-Navitoclax (ABT-263) Complex

Summary for 4LVT

• Entry DOI: 10.2210/pdb4lvt/pdb
• Related: 4LXD 4LXE
• Descriptor: Apoptosis regulator Bcl-2, 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide (3 entities in total)
• Functional Keywords: 8 helices, apoptosis regulator-inhibitor complex, apoptosis regulator/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Mitochondrion outer membrane ; Single-pass membrane protein : P10415
• Total number of polymer chains: 2
• Total formula weight: 40716.41

Authors

Park, C.H. (deposition date: 2013-07-26, release date: 2013-08-14, Last modification date: 2024-02-28)

Primary citation

Souers, A.J.,Leverson, J.D.,Boghaert, E.R.,Ackler, S.L.,Catron, N.D.,Chen, J.,Dayton, B.D.,Ding, H.,Enschede, S.H.,Fairbrother, W.J.,Huang, D.C.,Hymowitz, S.G.,Jin, S.,Khaw, S.L.,Kovar, P.J.,Lam, L.T.,Lee, J.,Maecker, H.L.,Marsh, K.C.,Mason, K.D.,Mitten, M.J.,Nimmer, P.M.,Oleksijew, A.,Park, C.H.,Park, C.M.,Phillips, D.C.,Roberts, A.W.,Sampath, D.,Seymour, J.F.,Smith, M.L.,Sullivan, G.M.,Tahir, S.K.,Tse, C.,Wendt, M.D.,Xiao, Y.,Xue, J.C.,Zhang, H.,Humerickhouse, R.A.,Rosenberg, S.H.,Elmore, S.W.
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
NAT.MED. (N.Y.), 19:202-208, 2013

PubMed Abstract: Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

PubMed: 23291630
DOI: 10.1038/nm.3048

Experimental method

X-RAY DIFFRACTION (2.05 Å)