Selective targeting of antiapoptotic BCL-2 proteins in cancer


Timucin A. C. , Basaga H., Kutuk O.

MEDICINAL RESEARCH REVIEWS, vol.39, no.1, pp.146-175, 2019 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Review
  • Volume: 39 Issue: 1
  • Publication Date: 2019
  • Doi Number: 10.1002/med.21516
  • Title of Journal : MEDICINAL RESEARCH REVIEWS
  • Page Numbers: pp.146-175
  • Keywords: antiapoptotic BCL-2 proteins, cancer, small molecules, targeted therapy, CHRONIC LYMPHOCYTIC-LEUKEMIA, BH3 MIMETIC ABT-737, CELL LUNG-CANCER, EFFICIENTLY INDUCES APOPTOSIS, MULTIPLE-MYELOMA CELLS, MCL-1 DOWN-REGULATION, SMALL-MOLECULE, HEPATOCELLULAR-CARCINOMA, RAF/MEK/ERK PATHWAY, IN-VITRO

Abstract

Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL2/ BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.