MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Abstract

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

Targeting of MCL-1 in breast cancer associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties

“…We also previously showed that in luminal breast cancers, MCL-1 expression in tumor cells was extrinsically favored by neighboring CAFs, which themselves exhibit high MCL-1 expression [13]. Our study thus brings support to the notion that a MCL-1 antagonist may improve the treatment of breast cancer [20,25] while putting forth an effect not only on cancer cells but also on non-malignant cells that interact with them. One implication is that the therapeutic potential of such a BH3 mimetic may be preclinically overlooked if reductive models using only tumor cells are used.…”

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

“…The most common cause of this is stabilization of Mcl-1 [140]. This, along with the fact that Mcl-1 is essential for the development and survival of AML cells, has led to the development of selective Mcl-1 inhibitors [141]. Sharon et al used CRISPR knockout screen to determine that ribosome-targeting antibiotics such as tedizolid can overcome venetoclax resistance by suppressing mitochondrial translation and respiration, and activating the cellular stress response [142].…”

Targeting CDK9 for Anti-Cancer Therapeutics

“…Therefore, combination of CDK9 inhibitors with those against MCL-1 could also significantly improve the effect of the CDK9 inhibitors. Several such inhibitors are undergoing clinical trials and have been reviewed elsewhere [178,179]. Other potential combinations could be with inhibitors of XIAP [180] had recently reported that inhibiting CDK9 activity with their newly developed inhibitor i-CDK9 suppressed phosphorylations of RNAP II at S2 and SPT5 at T775, induced genomewide pausing of RNAP II at gene promoters.…”