Document Detail


ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
MedLine Citation:
PMID:  23291630     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Andrew J Souers; Joel D Leverson; Erwin R Boghaert; Scott L Ackler; Nathaniel D Catron; Jun Chen; Brian D Dayton; Hong Ding; Sari H Enschede; Wayne J Fairbrother; David C S Huang; Sarah G Hymowitz; Sha Jin; Seong Lin Khaw; Peter J Kovar; Lloyd T Lam; Jackie Lee; Heather L Maecker; Kennan C Marsh; Kylie D Mason; Michael J Mitten; Paul M Nimmer; Anatol Oleksijew; Chang H Park; Cheol-Min Park; Darren C Phillips; Andrew W Roberts; Deepak Sampath; John F Seymour; Morey L Smith; Gerard M Sullivan; Stephen K Tahir; Chris Tse; Michael D Wendt; Yu Xiao; John C Xue; Haichao Zhang; Rod A Humerickhouse; Saul H Rosenberg; Steven W Elmore
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-06
Journal Detail:
Title:  Nature medicine     Volume:  19     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-07     Completed Date:  2013-04-17     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  202-8     Citation Subset:  IM    
Affiliation:
AbbVie Inc., North Chicago, Illinois, USA. andrew.souers@abbvie.com
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MeSH Terms
Descriptor/Qualifier:
Aniline Compounds / pharmacology
Animals
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Bicyclo Compounds, Heterocyclic / pharmacology*
Blood Platelets / drug effects*
Cell Survival / drug effects
Dogs
Female
HeLa Cells
Hematologic Neoplasms / drug therapy*
Humans
Mice
Mice, SCID
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  chemistry
Sulfonamides / pharmacology*
Tumor Burden
Xenograft Model Antitumor Assays
bcl-X Protein / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide; 0/Aniline Compounds; 0/Antineoplastic Agents; 0/Bicyclo Compounds, Heterocyclic; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 0/bcl-X Protein; XKJ5VVK2WD/navitoclax
Comments/Corrections
Comment In:
Nat Rev Clin Oncol. 2013 Feb;10(2):68   [PMID:  23337918 ]
Nat Rev Cancer. 2013 Feb;13(2):79   [PMID:  23344537 ]
Nat Med. 2013 Feb;19(2):131-3   [PMID:  23389605 ]

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