Preclinical study demonstrates selective antitumor efficacy of PRMT5 inhibitor AMG 193 in MTAP-deleted cancers, indicating strong therapeutic potential for targeted solid tumor treatment.
MTAP deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene CDKN2A . The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to S -adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making MTAP -deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor AMG 193, a molecule that inhibited the proliferation of HCT116 MTAP -deleted cells with ∼40x selectivity over HCT116 MTAP -WT cells. AMG 193 was orally efficacious in mouse xenografts of endogenous MTAP -null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that AMG 193 is brain-penetrant. AMG 193 is currently in Phase I/II clinical trials for the treatment of advanced MTAP -deleted solid tumors.
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Pettus et al. (2025) studied this question.
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