Anti-cancer drug discovery and development bcl-2 family small molecule inhibitors

Qiang Liu, Hong Gang Wang

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Deregulated apoptosis is a hallmark of cancer, and the B-cell lymphoma-2 (Bcl-2) family of proteins is pivotal to mediating the intrinsic pathway of this process. Recent advances have yielded both pan-Bcl-2 small molecule inhibitors (SMIs) that inhibit both the Bcl-2 and the Mcl-1 arm of the Bcl-2 family antiapoptotic proteins, as well as selective SMIs to differentially target the two arms. Of these SMIs, ABT-263 (navitoclax), AT-101 [(-)-gossypol], and obatoclax (GX15-070) are currently in clinical trials for multiple cancers. While pan-Bcl-2 inhibitors such as AT-101 and obatoclax can be more toxic for inhibiting all members of the anti-apoptotic Bcl-2 family of proteins, resistance can quickly develop for ABT-263, a selective Bcl-2 inhibitor. In this article, we discuss the current status of Bcl-2 family SMIs in preclinical and clinical development. As Mcl-1 upregulation is a major mechanism of ABT-263 resistance, Mcl-1-specific inhibitors are expected to be efficacious both in combination/sequential treatments and as a single agent against cancers resistant to ABT-263.

Original languageEnglish (US)
Pages (from-to)557-565
Number of pages9
JournalCommunicative and Integrative Biology
Volume5
Issue number6
DOIs
StatePublished - Nov 2012

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)

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