MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design

Kevin M. Cottrell ^*, Douglas A. Whittington, Kimberly J. Briggs, Haris Jahic, Janid A. Ali, Alvaro J. Amor, Deepali Gotur, Matthew R. Tonini, Wenhai Zhang, Alan Huang, and John P. Maxwell

Tango Therapeutics, 201 Brookline Ave, Boston, Massachusetts 02215, United States

*Email: kcottrell@tan-gotx.com

ABSTRACT

Deletion of the MTAP gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target MTAP-deleted cancer cells.

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