Overexpression of Mcl-1, a member of the Bcl-2 family that regulates apoptosis, is one cause of chemoresistance that is manifested as a consequence of sequestering the BH3 “death domains” of pro-apoptotic family members. Accordingly, the development of potent and selective inhibitors of Mcl-1 through BH3 mimicry is an area of intense research. The design of alkylating agents has experienced a renaissance recently. The surface of the Mcl-1 oncoprotein provides two opportunities to explore covalent inhibition: Lys234 near the p1 pocket of the canonical BH3-binding groove, and Cys286 located to the anterior of the aforementioned groove. A drug that can permanently modify a protein is expected to be especially potent as the k<sub>off</sub> rate should be negligible. However, this might translate into a clinical drug of limited efficacy if the reactive functional group does not permit discrimination between the intended target and all other biomolecules. Therefore, towards potent and selective inhibitors of Mcl-1, we have designed compounds that recognize the protein through non-covalent interactions and react reversibly with the protein. On the one hand, we have used structure-based design to modify existing BH3 mimetics to incorporate carbonyl-boronic acid warheads that can reversibly form iminoboronate adducts with Lys234. On the other hand, we have employed computer-aided drug design to develop reversible alkylating agents of Cys286 that feature an α-cyanoacrylamide/ester reactive functional group.<br/>

Covalent strategies towards the selective inhibition of the Mcl-1 oncoprotein

255th National Meeting (2018)

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