Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the BCL-2 family of proteins, and it is often upregulated in a diverse range of tumors, including breast cancer, non-small cell lung cancer, acute myeloid leukemia and multiple myeloma. Importantly, it has been demonstrated that Mcl-1 is essential for the growth of these tumors, hence the inhibition of Mcl-1 potentially affords a new avenue for the discovery of novel chemotherapies. While there have been notable successes in the selective antagonism of Mcl-1’s sister proteins Bcl-2 and Bcl-x<sub>L</sub> with small-molecules, the analogous selective inhibition of Mcl-1 has proven less fruitful, although clinical candidates are beginning to emerge. As a complementary strategy to our current approach where small-molecules are designed to delve deeply into the p2 pocket on the surface of the protein, we will present our progress on novel synthetic strategies to inhibit Mcl-1. Specifically, validated Mcl-1 inhibitors have been modified with chemical warheads towards the targeted covalent inhibition of the protein, while the grafting of thalidomide moieties is anticipated to cause the destruction of Mcl-1 through targeted hijacking of the cell’s protein degradation machinery.

Novel synthetic strategies to disarm the myeloid cell leukemia-1 oncoprotein

253rd National Meeting (2017)

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