Protein-protein interactions (PPIs) are central to many different cellular processes, and dysfunctional PPIs have been associated with disorders such as cancer and neurodegenerative diseases. The BCL-2 family of proteins is comprised of pro- and anti-apoptotic members. The PPIs between opposing BCL-2 family members within the cell are tightly regulated to ensure proper cellular function. Particularly, the anti-apoptotic proteins bind and neutralize their pro-apoptotic counterparts via their a-helical BH3 domains. In various cancers, including acute myeloid leukemia and multiple myeloma, there is an imbalance of the BCL-2 proteins, where anti-apoptotic proteins such as Bcl-2, Bcl-x<sub>L</sub>, and Mcl-1 are upregulated, leading to cell immortality and tumorigenesis. A validated strategy towards the inhibition of the anti-apoptotic proteins is through specific mimicry of key side chains projected from opposing faces of the BH3 a-helices with non-peptidic scaffolds. However, such rational designs are associated with lengthy synthesis and pan-BCL-2 inhibitory activities. With the emergence of selective Bcl-2 and Bcl-xL inhibitors, the development of selective Mcl-1 inhibitors represents an unmet medical need. Furthermore, expedited access to such inhibitors is desirable. Towards these ends, we will present our on-going work on the discovery of selective Mcl-1 inhibitors through the exploitation of the Kröhnke pyridine synthesis that accelerates access to a compound library of novel two-faced, synthetic a-helix mimetics.

Kröhnke pyridine synthesis permits facile access to novel Mcl-1 inhibitors

253rd National Meeting (2017)

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