Emerging Bcl-2 inhibitors for the treatment of cancer.
BACKGROUND
Bcl-2 family proteins are a component of the antiapoptotic machinery and are overexpressed in different malignancies. Accordingly, their enhanced expression has been attributed to the observed chemoresistance in most of the cancers. Therefore, targeting Bcl-2 family members becomes an important and attractive approach towards cancer therapy and is currently a very rapidly evolving area of research. This article highlights the numerous advancements that have been made in the design and synthesis of small molecule inhibitors (SMI) of pro-survival Bcl-2 proteins.


METHODS
This review comprehensively describes the progress made over the last 2 decades on this subject, including the clinical status of SMIs of Bcl-2 family proteins. Newer insights on the status of our knowledge on SMIs of Bcl-2 family proteins, their most beneficial application as well as current and future directions in this field are discussed.


CONCLUSIONS
Targeting Bcl-2 family proteins using SMI strategies is gaining momentum, with the emergence of certain new classes of inhibitors in Phase I and II clinical settings. In view of the tremendous progress toward the development of such inhibitors, this innovative approach certainly holds promise and has the potential to become a future mainstay for cancer therapy. The stage is set for the next generation of SMIs, for not only Bcl-2 proteins but also for Mcl-1. Other emerging molecules in the apoptotic machinery will also be explored and targeted.
Azmi
Asfar S
AS
Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, Barbara Ann Karmanos Cancer Institute, Department of Pathology, 4100 John R, Detroit, MI 48201, USA.
Wang
Zhiwei
Z
Philip
Philip A
PA
Mohammad
Ramzi M
RM
Sarkar
Fazlul H
FH
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries
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