prt543

PRT543 is an orally available, potent, and selective small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5). PRMT5 is an enzyme responsible for the symmetrical dimethylation of arginine residues on target proteins, a post-translational modification essential for normal RNA splicing and gene expression. Aberrant PRMT5 activity has been implicated in cancer progression due to its role in regulating cell growth and survival. PRT543 inhibits the methyltransferase activity of the PRMT5/MEP50 complex with high potency (IC50 = 10.8 nM), leading to antiproliferative and antineoplastic effects in vitro and in vivo. Preclinical studies have shown that PRT543 downregulates genes involved in RNA splicing and DNA damage repair by promoting alternative splicing, resulting in synthetic lethality particularly in cancers with spliceosomal mutations such as SF3B1-mutant uveal melanoma or myeloid malignancies. Clinically, PRT543 has demonstrated safety and tolerability at a dose of 35 mg five times per week, with ongoing phase I trials evaluating its efficacy as monotherapy for advanced solid tumors, myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), MDS/myeloproliferative neoplasm overlap syndromes, and other hematological malignancies[1][2][3][4][5][6][7].