Therapeutics targeting Bcl-2 in hematological malignancies

Biochem J. 2017 Oct 23;474(21):3643-3657. doi: 10.1042/BCJ20170080.

Abstract

Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications. Additional selective antagonists of Bcl-2 family members, including Bcl-XL and Mcl-1, are in various stages of preclinical and clinical development and hold the promise of extending clinical utility beyond CLL and overcoming resistance to venetoclax. In addition to direct targeting of Bcl-2 family proteins with BH3 mimetics, combination therapies that aim at down-regulating expression of anti-apoptotic BCL-2 family members or restoring expression of pro-apoptotic BH3 family proteins may provide a means to deepen responses to venetoclax and extend the utility to additional indications. Here, we review recent progress in direct and selective targeting of Bcl-2 family proteins for cancer therapy and the search for rationale combinations.

Keywords: Bcl-2; apoptosis; hematological malignancy.

Publication types

  • Review

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Drug Delivery Systems / methods*
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / metabolism
  • Hematologic Neoplasms / pathology
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sulfonamides / therapeutic use*
  • bcl-X Protein / antagonists & inhibitors
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • BCL2 protein, human
  • BCL2L1 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • venetoclax