4MAN

Bcl_2-Navitoclax Analog (with Indole) Complex

「4LXE」から置き換えられました

4MAN の概要

• エントリーDOI: 10.2210/pdb4man/pdb
• 関連するPDBエントリー: 4LVT 4LXD
• 分子名称: Apoptosis regulator Bcl-2, 4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide (3 entities in total)
• 機能のキーワード: 8 helices, apoptosis regulator-inhibitor complex, apoptosis regulator/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Mitochondrion outer membrane ; Single-pass membrane protein : P10415
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40560.09

構造登録者

Park, C.H. (登録日: 2013-08-16, 公開日: 2014-01-29, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.07 Å)