4.7 Review

Discovery of cysteine-targeting covalent histone methyltransferase inhibitors

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Summary: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in hematologic and solid tumors, and its methyltransferase function is associated with tumor cell proliferation and overall survival. The discovery of potent and selective PRMT5 inhibitors, such as PF-06939999, has provided a potential approach for targeting cancer-specific dependencies. Inhibition of PRMT5 by PF-06939999 reduces proliferation and affects alternative splicing in non-small cell lung cancer (NSCLC) cells. The efficacy of PF-06939999 in mouse tumor xenograft models with splicing mutations suggests its therapeutic potential in the treatment of NSCLC with splicing dysregulation.

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