Bcl-2 antagonists: a proof of concept for CLL therapy

Abstract

Defective apoptosis is a fundamental hallmark feature of CLL biology and is a major target of cancer therapy development. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. While several approaches were considered to selectively inhibit Bcl-2 family anti-apoptotic proteins, the discovery that gossypol binds and antagonizes anti-apoptotic effect of Bcl-2 family proteins was a major breakthrough in identifying specific Bcl-2 antagonists. The concept of mimicking BH3 domain emphasized the importance of Bcl-2 family-targeted therapy that can modulate the function of anti-apoptotic proteins. Although parent compound gossypol did not sustain in the clinic, its structural modifications led to the development of additional analogues that demonstrated improved efficacy and reduced toxicity in preclinical and clinical investigations. Proof of concept of this hypothesis was demonstrated by structure based BH3 mimetic ABT-737 that has shown greater cytotoxicity towards CLL cells both in pre-clinical models and clinical trials. Its oral compound ABT-263 has demonstrated the substantial susceptibility of chronic lymphocytic leukemia cells through Bcl-2 inhibition. Collectively, results of a Phase I Study of Navitoclax (ABT-263) in patients with relapsed or refractory disease warrants Bcl-2 as a valid therapeutic target in CLL. Importantly, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Mcl-1, Bcl-2 and Bcl-XL.

Gossypol Increases Expression of the Pro-apoptotic BH3-only Protein NOXA through a Novel Mechanism Involving Phospholipase A2, Cytoplasmic Calcium, and Endoplasmic Reticulum Stress

“…Gossypol is still commonly described as a BCL2/BCLXL inhibitor (50). We and others have generated substantial data showing that gossypol does not directly inhibit BCL2 proteins in cells.…”

The re-emergence of natural products for drug discovery in the genomics era

“…Although earlier trials with racemic gossypol were not successful, a single enantiomer of gossypol (called AT-101) is now in clinical trials in patients with different forms of cancer 253 . Newer analogues of gossypol are also being tested in cancer 254 , but it remains to be seen whether or not they will be successful. Thus, the experimental studies with gossypol paved the way to synthetic inhibitors of BCL-2 that are now in clinical trials 254 .…”

“…Newer analogues of gossypol are also being tested in cancer 254 , but it remains to be seen whether or not they will be successful. Thus, the experimental studies with gossypol paved the way to synthetic inhibitors of BCL-2 that are now in clinical trials 254 .…”

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

“…Many of the Bcl-2 antagonists currently being investigated are BH3-mimetics (Lessene et al, 2008). Compounds such as Venetoclax and Navitoclax mimic the BH3 binding domain present in pro-apoptotic molecules and bind with higher affinity to anti-apoptotic Bcl-2 family proteins (Balakrishnan & Gandhi, 2013; Cummins et al, 2016b), blocking their anti-apoptotic function thereby favouring apoptosis. Venetoclax has recently been licensed for the treatment of chronic lymphocytic leukaemia (CLL) and is in advanced clinical development for non-Hodgkin’s lymphoma (NHL) (Souers et al, 2013).…”