ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets | Zendy

Andrew J. Souers | Zendy; Joel D. Leverson | Zendy; Erwin R. Boghaert | Zendy; Scott Ackler | Zendy; Nathaniel D. Catron | Zendy; Jun Chen | Zendy; Brian D. Dayton | Zendy; Hong Ding | Zendy; Sari H. Enschede | Zendy; Wayne J. Fairbrother | Zendy; David C.S. Huang | Zendy; S.G. Hymowitz | Zendy; Sha Jin | Zendy; Seong Lin Khaw | Zendy; Peter Kovar | Zendy; Lloyd T. Lam | Zendy; Jackie Lee | Zendy; Heather Maecker | Zendy; Kennan C. Marsh | Zendy; Kylie D. Mason | Zendy; Michael J. Mitten | Zendy; Paul Nimmer | Zendy; Anatol Oleksijew | Zendy; Chang H. Park | Zendy; CheolMin Park | Zendy; Darren C. Phillips | Zendy; Andrew W. Roberts | Zendy; Deepak Sampath | Zendy; John F. Seymour | Zendy; Morey L. Smith | Zendy; Gerard M. Sullivan | Zendy; Stephen K. Tahir | Zendy; Chris Tse | Zendy; Michael Wendt | Zendy; Xiao Yu | Zendy; John Xue | Zendy; Haichao Zhang | Zendy; Rod A. Humerickhouse | Zendy; Saul H. Rosenberg | Zendy; Steven W. Elmore | Zendy

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ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

Author(s) -

Andrew J. Souers,

Joel D. Leverson,

Erwin R. Boghaert,

Scott Ackler,

Nathaniel D. Catron,

Jun Chen,

Brian D. Dayton,

Hong Ding,

Sari H. Enschede,

Wayne J. Fairbrother,

David C.S. Huang,

S.G. Hymowitz,

Sha Jin,

Seong Lin Khaw,

Peter Kovar,

Lloyd T. Lam,

Jackie Lee,

Heather Maecker,

Kennan C. Marsh,

Kylie D. Mason,

Michael J. Mitten,

Paul Nimmer,

Anatol Oleksijew,

Chang H. Park,

CheolMin Park,

Darren C. Phillips,

Andrew W. Roberts,

Deepak Sampath,

John F. Seymour,

Morey L. Smith,

Gerard M. Sullivan,

Stephen K. Tahir,

Chris Tse,

Michael Wendt,

Xiao Yu,

John Xue,

Haichao Zhang,

Rod A. Humerickhouse,

Saul H. Rosenberg,

Steven W. Elmore

Publication year - 2013

Publication title -

nature medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.536

H-Index - 547

eISSN - 1546-170X

pISSN - 1078-8956

DOI - 10.1038/nm.3048

Subject(s) - chronic lymphocytic leukemia , cancer research , apoptosis , venetoclax , in vivo , bcl 2 family , lymphoma , leukemia , cancer , pharmacology , cancer cell , platelet , chemistry , programmed cell death , biology , medicine , immunology , biochemistry , microbiology and biotechnology

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.

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