Emerging Bcl-2 inhibitors for the treatment of cancer

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.