General AML

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Various therapeutic advancements have improved the treatment of Acute Myeloid Leukemia (AML) over the few last decades; from chemotherapy to bone marrow transplants. Currently, small molecule inhibitors may provide the next therapeutic breakthrough in the management of AML.

Since the inappropriate management of apoptosis is major factor in the development of AML and other cancers, targeting proteins of the Bcl-2 family, which regulate apoptosis, has been a useful approach. According to András Kotschy et al. there are already some novel agents in development, which target members of the Bcl-2 family, including: BCL-2, BCL-XL and BCL-W (navitoclax, ABT-263) or BCL-2 alone (venetoclax, ABT-199).

Recent studies on the development of leukemia have revealed that the pro-survival protein Myeloid Cell Leukemia 1 (MCL-1) is overexpressed in AML.

Researchers have also discovered that the small molecule S63845 binds to the BH3-binding groove of MCL1. At present, there are not any MCL1 inhibitors in development for the treatment of AML. Although, development of such an agent would require caution since MCL1 is vital for the survival of hematopoietic stem cells and other important cell types.

András Kotschy et al. are the first researchers to report on the mechanism of action of S63845 in cancer-derived cell lines in vitro and in vivo in preclinical mouse models. They investigated the effects of S63845 in 25 AML patient samples alongside ABT-199 and the standard-of-care drugs, idarubicin and ara-C. In addition, the effects of S63845 were analyzed in mouse models.

The key findings demonstrated that S63845 had a selective apoptotic effect on in vivo and in vitro AML samples compared to that of healthy donor hematopoietic stem cells. Furthermore, S63845 disrupted the binding of BAK and BAX to MCL1 in HeLa cells, whereas the molecule had no impact on the interaction of these pro-apoptotic proteins with BCL-XL or BCL-2.

The authors conclude that this study provides pre-clinical evidence of the safety and efficacy of MCL1 inhibition in AML therapy.

The study was published in Nature in October 2016. Please see the abstract below:

 

Abstract

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

References
  1. Kotschy A. et al.The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19. DOI: 10.1038/nature19830. [Epub ahead of print]