From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors

Abstract

Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-X dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer. Clinical experience with navitoclax prompted the generation of the highly selective BCL-2 inhibitor venetoclax, which is now approved in the United States for the treatment of patients with chronic lymphocytic leukaemia with 17p deletion who have received at least one prior therapy. Recent advances have also been made in the development of potent and selective inhibitors of BCL-X and myeloid cell leukaemia 1 (MCL1), which are additional BCL-2 family members with established anti-apoptotic roles in cancer. Here we review the latest progress in direct and selective targeting of BCL-2 family proteins for cancer therapy.

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

“…BH3 mimetics are small compounds that antagonize anti-apoptotic BCL-2 family proteins, leading to apoptosis induction in cancer cells 3,4,39 . Similar to the BH3 domain in BH3-only proteins, BH3 mimetics specifically interact with anti-apoptotic BCL-2 family proteins and disrupt their ability to interact with pro-apoptotic BCL-2 proteins to induce BAX/BAK-dependent apoptosis 2,39 .…”

Bcl-2 on the brink of breakthroughs in cancer treatment

“…Since its discovery in B-cell lymphomas over 30 years ago, research on the biological functions and mechanisms of action of Bcl-2 family proteins in controlling cell life and death decisions has revealed important roles in multiple diseases, paving the way for at least one novel therapeutic agent. 1,2 In this issue of Cell Death and Differentiation, several of the world's leaders in research on Bcl-2 family proteins provide complementary reviews covering multiple facets of this intriguing class of proteins, ranging from cellular and molecular mechanistic insights about how these proteins work and addressing their roles in evolution of programmed cell death mechanisms, mammalian development, cancer genetics, cancer biology and applications towards novel cancer therapies. [3][4][5][6][7][8][9] With the recent approval by FDA of the orally bioavailable and highly selective Bcl-2 inhibitor, venetoclax, for some subtypes of chronic lymphocytic leukemia (CLL), Bcl-2 family proteins are now validated as promising drug targets, with the potential to provide significant advances in the standard of care for patients suffering from oncological maladies and possibly for certain non-oncological diseases as well.…”

First targeted therapy in multiple myeloma

“…2 Recent studies have demonstrated that the specific composition of the TME can be associated with treatment outcomes, and specifically, the number of tumor-associated macrophages has been shown in multiple studies to predict shorter survival after standard-of-care chemotherapy. 3 The biological and clinical importance of the TME is highlighted by novel therapeutic approaches designed to target the various constituent elements of and the cellular crosstalk within the TME. …”

“…3 BCL-2 is an inhibitor of intrinsic apoptosis signals (thus, a mediator of tumor growth), and overexpression of antiapoptotic BCL-2 has been correlated with chemoresistance. Venetoclax has shown antitumor effects in various malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), through binding to BCL-2 and induction of tumor cell apoptosis.…”