PRMT5 is a type II protein arginine <i>N</i>-methyl transferase which employs <i>S</i>-adenosyl methionine (SAM) as a co-factor for symmetric dimethylation of protein arginine residues. The targeting of arginine methylation by PRMT5 is a novel mechanism for treating cancer which seeks to exploit splicing vulnerabilities within malignant cells that are dependent on alternative splicing. The design and synthesis of a series of PRMT5 inhibitors bearing a carbonucleoside core will be described. Highlighted will be the synthetic strategy deployed to assemble all four contiguous stereocenters asymmetrically utilizing a palladium catalyzed desymmetrization approach. Furthermore, we will describe high-throughput experimentation efforts, characterization studies, and methodology development en route to the synthesis of novel tetrahydroisoquinolines via rhodium catalyzed C-H activation. We will conclude with the discovery and profile of our clinical candidate PF-06939999.

Design and synthesis of carbonucleoside inhibitors of PRMT5 for the treatment of cancer: A desymmetrization approach

ACS Spring Meeting 2021

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