Discovery of MTA-Cooperative PRMT5 Inhibitors for the Treatment of MTAP-Deleted Cancer.

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PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions via symmetric dimethylation of target proteins involved in spliceosome regulation, cell cycle progression, apoptosis, the DNA-damage response, and other functions. PRMT5 dependence in cells with MTAP deletions is a strong and prevalent synthetic lethal interaction. Due to their mechanisms of action, existing clinical PRMT5 inhibitors do not recapitulate the selectivity for MTAPnull cells demonstrated by genetic perturbation. Given that MTAP deletion occurs in approximately 10-15% of all human cancer, a molecule that selectively kills MTAPnull cancer cells provides an important opportunity to deliver a targeted treatment to a significant patient population. We have discovered small molecules that exhibit MTA-cooperative PRMT5 binding and selectively kill MTAPnull cancer cells. Striking MTAP-dependent viability effects are demonstrated in MTAP-isogenic cell lines representing multiple lineages, and in a multi-lineage cell line panel comprised of 200 cancer cell lines. Furthermore, oral administration of an MTAPnull -selective PRMT5 inhibitor demonstrates dose-dependent antitumor activity and strong regressions across multiple histologies in both cancer cell line and patient-derived xenografts. These data strongly suggest the therapeutic potential of MTAPnull -selective PRMT5 inhibitors in MTAP-deleted cancers. A Phase 1/2 clinical trial (NCT05275478) is currently enrolling to assess safety, tolerability, and efficacy in patients with advanced or metastatic MTAP-deleted solid tumors.

Presented by Dr. Alan Huang, PhD, Chief Scientific Officer of Tango Therapeutics.

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