BH3 Mimetics for the Treatment of B-Cell Malignancies—Insights and Lessons from the Clinic

Abstract

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.

Engeletin Protects Against TNF-α-Induced Apoptosis and Reactive Oxygen Species Generation in Chondrocytes and Alleviates Osteoarthritis in vivo

“…Cytochrome c is then released from the mitochondria and activates the caspase cascade, initiating the apoptotic process. 31–34 The present study showed that engeletin maintained mitochondrial membrane potential and alleviated chondrocyte apoptosis by upregulating Bcl-2 expression and inhibiting Bax expression.…”

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

“…Since the approval of venetoclax for chronic lymphocytic leukemia, BH3 mimetics have bloomed as potential treatments for multiple types of cancer, predominantly hematological ( Valentin et al, 2018 ). Despite impressive experimental and clinical results as single agents, increasing evidence showed that BH3 mimetics real potential is enhancing other anti-cancer agents, both conventional chemotherapy and targeted ( Montero and Letai, 2018 ; Oudenaarden et al, 2018 ; Savona and Wei, 2019 ; Lin et al, 2020 ). Numerous studies have demonstrated that cancer cells often rely on anti-apoptotic proteins to acquire resistance to therapy, and BH3 mimetics can effectively block these adaptations ( Hata et al, 2015 ; Maji et al, 2018 ).…”

Inhibition of MCL1 induces apoptosis in anaplastic large cell lymphoma and in primary effusion lymphoma

“…The aberrant expression of BCL2 and of other members of the BCL2 family is well-described in follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and in acute myeloid leukemia (AML) 3 , 4 . Mimicking proapoptotic BH3-only proteins, BH3 mimetics antagonize the function of antiapoptotic BCL2 family proteins, providing a new opportunity for treatment of these diseases 3 , 4 . Antagonizing BCL2, venetoclax was the first BH3 mimetic approved for CLL and then—in combination with hypomethylating drugs—also for AML 1 , 5 .…”