Editors' ChoiceCancer

BH3 mimetics: Weapons of cancer cell destruction

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Science Translational Medicine  16 Jan 2019:
Vol. 11, Issue 475, eaaw5311
DOI: 10.1126/scitranslmed.aaw5311

Abstract

Specific MCL-1 inhibitor kills multiple myeloma and acute myeloid leukemia cells.

Certain cancer cells are ”primed” to die. During the oncogenic transformation, some cancer cells become reliant on continuous expression of an anti-apoptotic protein, such as myeloid cell leukemia 1 (MCL-1). MCL-1 becomes ”primed” with prodeath proteins, such as BCL-2 homologous antagonist/killer (BAK), and inhibition with small molecular inhibitors, called BCL-2 homology domain-3 (BH3) mimetics, selectively kills the cancer cells. MCL-1 is of particular interest as a therapeutic target because it is one of the most frequently amplified genes across all human cancer, and increased expression of MCL-1 is associated with chemotherapy resistance. The making of specific inhibitors to MCL-1 has been challenging, in part due to its long shallow hydrophobic groove, but there has been great progress of late. A recent paper by Tron and colleagues reports the development of a specific MCL-1 inhibitor, AZD5991.

Similar to the development of other BH3 mimetics, the authors used a diverse range of lead generation strategies, including fragment-based lead generation and structure-based drug design, to discover the macrocyclic MCL-1 inhibitor AZD5991. To prove on-target activity, it is important to show that prodeath proteins, such as BAK, are released from MCL-1 after addition of the small molecule inhibitor. Here, they show that AZD5991 inhibits the interaction of MCL-1 and BAK in tumor cells and that BAK is required to induce cell death. They then screened a panel of 142 cancer cell lines, including both hematological and solid cancers, for sensitivity to MCL-1 inhibition. They determined that acute myelogenous leukemia (AML), multiple myeloma (MM), non-Hodgkin lymphoma, and certain lung and breast cancer cell lines were sensitive to MCL-1 inhibition. Next, they tested it in vivo, in subcutaneous models of MM and AML, and found a reduction in tumor volume, even after a single treatment.

One concern with MCL-1 BH3 mimetics is the side effects caused by on-target inhibition of MCL-1 in normal cells. We have learned from knock-out mouse studies that MCL-1 plays an important role in diverse tissues. The MCL-1 inhibitors in development, including AZD9551, are less effective at inhibiting mouse MCL-1 than its human counterpart. Therefore, the preclinical mouse studies may not necessary elucidate the on-target side effects. Clinical trials are currently underway to assess the efficacy of MCL-1 inhibitors, which have huge clinical potential either as single agents or in combination regimens, as long as MCL-1–dependent tumors can be accurately identified and as long as the side effects are manageable.

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