Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature medicine, 2013-02, Vol.19 (2), p.202-208

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Inhibition of prosurvival proteins of the BCL family is a promising anticancer strategy; however, the similarities between the family members make the development of specific agents difficult. Current compounds have been designed to target BCL-2, which is frequently elevated in tumors and is an important prosurvival factor, but also inhibit BCL-X L , which is required for the survival of platelets; thus, thrombocytopenia is a limiting toxic effect in patients. The authors have engineered anti-BCL drugs to generate a more BCL-2–specific compound that has less affinity for BCL-X L and, therefore, reduced platelet toxicity. The compound is effective in several tumor models in vivo and had reduced toxicity in three patients with refractory leukemia, showing a promising activity and safety profile to refine and improve proapoptotic therapy in cancer. 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.