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

Authors :
Souers, Andrew J.
Leverson, Joel D.
Boghaert, Erwin R.
Ackler, Scott L.
Catron, Nathaniel D.
Chen, Jun
Dayton, Brian D.
Ding, Hong
Enschede, Sari H.
Fairbrother, Wayne J.
Huang, David C.S.
Hymowitz, Sarah G.
Jin, Sha
Khaw, Seong Lin
Kovar, Peter J.
Lam, Lloyd T.
Lee, Jackie
Maecker, Heather L.
Marsh, Kennan C.
Mason, Kylie D.
Mitten, Michael J.
Nimmer, Paul M.
Oleksijew, Anatol
Park, Chang H.
Park, Cheol-Min
Phillips, Darren C.
Roberts, Andrew W.
Sampath, Deepak
Seymour, John F.
Smith, Morey L.
Sullivan, Gerard M.
Tahir, Stephen K.
Tse, Chris
Wendt, Michael D.
Xiao, Yu
Xue, John C.
Zhang, Haichao
Humerickhouse, Rod A.
Rosenberg, Saul H.
Elmore, Steven W.
Source :
Nature Medicine. February 1, 2013, Vol. 19 Issue 2, p202, 9 p.
Publication Year :
2013

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.sub.L]), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by [BCL-X.sub.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.<br />Apoptosis, or programmed cell death, is a conserved and regulated process that is the primary mechanism for the removal of aged, damaged and unnecessary cells. The ability to block apoptotic [...]

Details

Language :
English
ISSN :
10788956
Volume :
19
Issue :
2
Database :
Gale General OneFile
Journal :
Nature Medicine
Publication Type :
Academic Journal
Accession number :
edsgcl.320847271
Full Text :
https://doi.org/10.1038/nm.3048