Therapeutic inhibition of BCL-2 and related family members

ABSTRACT

Introduction: BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell’s ability to evade programmed cell death.

Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family. BH3 profiling is reviewed. Historical therapeutic agents are addressed, and currently investigated BH3 mimetics are described with attention to clinical significance. The limitations of BCL-2 family targeted drugs with regard to on-target and off-target toxicities are explored. Agents under development for targeting MCL-1 and other BCL-2 family members are discussed.

Expert opinion: ABT-199 (venetoclax) and other BH3 mimetics have entered the clinical arena and show promising results in both hematologic and solid malignancies. Use of agents targeting this system will likely expand, and likely a number of malignant diseases will be successfully targeted resulting in improved treatment responses and patient survival.

KEYWORDS:

• BCL-2
• apoptosis
• BH3 mimetics
• targeted therapy

Article highlights

• BCL-2 family of proteins are well understood to play a significant role in apoptosis.

• Some mechanisms by which cancer cells evade apoptosis have been shown to rely on alterations in the dynamic interplay between BCL-2 family member proteins.

• BH3 profiling is beginning to enable a better understanding of specific mechanisms by which tumors evade apoptosis, and subsequently target these mechanisms.

• The BCL-2 system of proteins has been targeted with a series of BH-3 mimetic and other small molecules, several of which have entered clinical studies.

• Venetoclax, the first FDA-approved BCL-2 inhibitor, is effective in CLL and is showing promise in other hematologic malignancies.

• This box summarizes key points contained in the article.

Declaration of interest

D. Claxton has previously received prior clinical research funding for obatoclax. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.