BH3-mimetics: recent developments in cancer therapy

Abstract

The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

“…The development of inhibitors targeting Mcl-1 is increasing in interest, and in recent years significant progress has been made in designing highly selective Mcl-1 inhibitors. Until now, 36 compounds have entered phase I clinical trials and are being evaluated for the treatment of recurrent or refractory hematologic malignancies [ 156 , 157 ]. In the case of breast cancer, Mcl-1 inhibitors have shown promising activity in preclinical studies.…”

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

“…Accordingly, the approach of targeting BCL-2 proteins has been pursued for cancer treatment. Over the last ten years, “BH3-mimetics” drugs—that mimic the pro-apoptotic functions of the BH3 domains of Bcl-2 proteins—have been the principal approach to blocking the anti-apoptotic function of Bcl-2 family members [ 237 ]. Although several agents have been tested in preclinical and clinical studies, only ABT-199 (venetoclax) has been approved by the FDA for the treatment of patients with (1) CLL; (2) SLL patients; and (3) newly diagnosed AML-aged 75 years or older, or who have comorbidities precluding intensive induction chemotherapy, in combination with azacitidine or decitabine or low-dose cytarabine (LDAC) [ 10 , 236 , 238 , 239 , 240 ].…”

Bioprospecting macroalgae, marine and terrestrial invertebrates & their associated microbiota

“…Prodigiosin (Figure 3) was first isolated from Serratia marcescens, in 1962, but it is produced in many gram positive and gram negative bacteria. Its chemical structure, actually, inspired the development of obatoclax, a BH3 mimetic synthetic compound that acts as a pharmacological pan-inhibitor of anti-apoptotic members of the BCL2 family, and reached clinical trials for leukemia and lymphoma patients (Townsend et al 2021).…”