AMG-193

AMG 193 is an orally active MTA-cooperative PRMT5 inhibitor with antitumor activity. AMG 193, when complexed with MTA, preferentially inhibits the growth of MTAP-deficient tumor cells by inhibiting PRMT5 ( IC₅₀ =0.107 μM), thereby protecting normal cells with wild-type MTAP ^{[1] [2]}.

In Vivo, AMG 193 (3-100 mg/kg; p.o.; once every 5 days for 4 doses) dose-dependently inhibits tumor growth in MTAP-deficient xenograft mice^[2]. AMG 193 (100 mg/kg; p.o.; once daily for 11 days) slightly reduces body weight in mice implanted with DLBCL (DOHH-2) tumors and causes tumor regression in 70% of mice, with preservation of normal hematopoietic cell lineages^[2].

In Vitro, AMG 193 (200 μM; 6 d) induces alternative splicing defects, cell cycle arrest, and DNA damage response in MTAP-deficient HCT116 cells^[2].

References:
[1]. Belmontes B, et al. Abstract B177: The discovery and preclinical characterization of AMG 193, a first-in-class MTA-cooperative PRMT5 inhibitor with broad activity against MTAP-null cancers[J]. Molecular Cancer Therapeutics, 2023, 22(12_Supplement): B177-B177.
[2]. Belmontes B, et al. AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers[J]. Cancer Discovery, 2024: OF1-OF23.