MCL-1 inhibition in cancer treatment

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MCL-1 inhibition in cancer treatment

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Author(s): Weiguo Xiang ¹ , Chao-Yie Yang ¹ ^, ² , Longchuan Bai ¹ ^, ²

Publication date (Electronic): 23 October 2018

Journal: OncoTargets and therapy

Publisher: Dove Medical Press

Keywords: BCL-2, BAX, BAK, apoptosis, BH3 mimetics

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Abstract

Myeloid cell leukemia-1 (MCL-1), a member of antiapoptotic BCL-2 family proteins, is a key regulator of mitochondrial homeostasis. Frequent overexpression of MCL-1 in human primary and drug-resistant cancer cells makes it an attractive cancer therapeutic target. Significant progress has been made in the development of small-molecule MCL-1 inhibitors in recent years, and three MCL-1 selective inhibitors have advanced to clinical trials. This review briefly discusses recent advances in the development of small molecules targeting MCL-1 for cancer therapy.

Most cited references 82

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Mechanisms of action of Bcl-2 family proteins.

Aisha Shamas-Din, Justin Kale, Brian Leber … (2013)

The Bcl-2 family of proteins controls a critical step in commitment to apoptosis by regulating permeabilization of the mitochondrial outer membrane (MOM). The family is divided into three classes: multiregion proapoptotic proteins that directly permeabilize the MOM; BH3 proteins that directly or indirectly activate the pore-forming class members; and the antiapoptotic proteins that inhibit this process at several steps. Different experimental approaches have led to several models, each proposed to explain the interactions between Bcl-2 family proteins. The discovery that many of these interactions occur at or in membranes as well as in the cytoplasm, and are governed by the concentrations and relative binding affinities of the proteins, provides a new basis for rationalizing these models. Furthermore, these dynamic interactions cause conformational changes in the Bcl-2 proteins that modulate their apoptotic function, providing additional potential modes of regulation.

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Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

J D Leverson, H. Zhang, J J Chen … (2015)

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

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Targeted protein degradation by PROTACs.

Taavi Neklesa, James D Winkler, Craig M Crews (2017)

Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and degradation of the target protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins. Herein, we highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700-1000Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years.

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Author and article information

Journal

Journal ID (nlm-ta): Onco Targets Ther

Journal ID (iso-abbrev): Onco Targets Ther

Journal ID (publisher-id): OncoTargets and Therapy

Title: OncoTargets and therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1178-6930

Publication date Collection: 2018

Publication date (Electronic): 23 October 2018

Volume: 11

Pages: 7301-7314

Affiliations

[1 ]Department of Internal Medicine, University of Michigan Medical School, lbai@ 123456umich.edu

[2 ]Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA, lbai@ 123456umich.edu

Author notes

Correspondence: Longchuan Bai, Rogel Cancer Center, University of Michigan, 1600 Huron Parkway, Bldg 520-G352, Ann Arbor, MI 48105, USA, Tel +1 734 647 5111, Fax +1 734 647 9647, Email lbai@ 123456umich.edu

Article

Publisher ID: ott-11-7301

DOI: 10.2147/OTT.S146228

PMC ID: 6205821

PubMed ID: 30425521

SO-VID: b33f3a41-44d2-4537-a015-81f9c1c227f1

License:

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