Preclinical Activity of the Clinical Stage Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor PRT543 in Splicing Mutant Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

MDS and AML are generally incurable malignancies that need newer therapeutic options, as the disease-initiating stem cells are not eliminated by conventional therapies. Splicing factor mutations account for approximately 50% of mutations in MDS. Among those are SF3B1 and U2AF1 mutations, which are related to pathogenesis of disease by overactivation of oncogenic pathways, such as Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) signaling. Via activation of IRAK4 and other pathways, spliceosome mutations can lead to a block in differentiation and malignant proliferation. PRMT5 is an enzyme involved in spliceosome complex formation and fidelity and is over-expressed in patients with MDS/AML. The inhibition of PRMT5 may contribute to stem/progenitor cell differentiation rather than aberrant proliferation in an undifferentiated immature state. The objective of this study is to determine the activity of a clinical stage PRMT5 inhibitor, PRT543, in subtypes of MDS/AML using cell lines and primary samples. In preclinical studies PRT543 showed broad antitumor activity in vitro and in vivo (Bhagwat AACR 2020) and is currently under investigation in a Phase I clinical trial in patients with myeloid malignancies.