Synthetic Lethality

Cancer Target Rationale

Accumulation of 5’-methylthiodenosine (MTA) in tumors by the loss of its metabolizing enzyme methylthioadenosine phosphorylase (MTAP) results in partial inhibition of protein arginine methyltransferase 5 (PRMT5), an essential enzyme for multiple cellular functions including transcription, cellular differentiation, and proliferation.1,2 Pharmacological inhibition of methionine adenosyltransferase 2 alpha (MAT2A), a key enzyme for S-adenosylmethionine (SAM) synthesis, exacerbates PRMT5 inhibition by depleting its substrate and inducing synthetic lethality in cancers harboring MTAP loss.1,3

Overview

GSK4362676 (IDE397) is a MAT2A inhibitor being investigated as a synthetically lethal monotherapy for MTAP-deleted solid tumors.1,4

References

  1. Marjon K, Cameron MJ, Quang P, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 2016;15(3):574-587.
  2. Stopa N, Krebs JE, Shechter D. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell Mol Life Sci. 2015;72(11):2041-2059.
  3. Fisher MM, Bhola N, Faulhaber J, et al. MAT2A inhibitor, IDE397, displays broad anti-tumor activity across a panel of MTAP-deleted patient-derived xenografts. Poster presented at: American Association for Cancer Research Annual Meeting; April 10-15, 2021. Poster 1278.
  4. ClinicalTrials.gov. Accessed June 14, 2021. www.clinicaltrials.gov/