Protein Arginine Methyl Transferase 5 (PRMT5) is an enzyme that symmetrically places two methyl groups onto its substrate proteins, which include histones, transcription factors, and components of the spliceosome. PRMT5 thereby controls multiple critical cellular processes including transcription, translation, and DNA repair, and regulates the expression of genes involved in promoting cancer cell growth and survival. Overexpression and increased enzymatic activity of PRMT5 has been associated with poor outcomes and decreased survival in multiple human cancer settings and is believed to mediate cancer progression in certain solid tumors, lymphomas, and myeloid malignancies.
Selective inhibition of PRMT5 has been shown to decrease tumor growth, reverse resistance, and improve survival in preclinical models. PRMT5 inhibition has also been shown to downregulate DNA damage repair genes, resulting in synthetic lethality in homologous recombination deficient positive (HRD+) tumors.
Prelude rationally designed and synthesized more than 600 compounds during the optimization of our lead PRMT5 inhibitors, not only to improve potency and selectivity, but to simultaneously build in desired pharmaceutical properties.