TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor developed for the treatment of MTAP-deleted cancers.

in Translational oncology by Kimberly J Briggs, Kevin M Cottrell, Matthew R Tonini, Alice Tsai, Minjie Zhang, Douglas A Whittington, Wenhai Zhang, Steven A Lombardo, Satoshi Yoda, Erik W Wilker, Samuel R Meier, Yi Yu, Teng Teng, Alan Huang, John P Maxwell

TLDR

  • TNG908, a clinical stage PRMT5 inhibitor, has a unique binding mechanism that selectively targets MTAP-null cancers, demonstrating strong preclinical activity and potential for histology-agnostic clinical development.

Abstract

TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).

Overview

  • The study focuses on the clinical stage PRMT5 inhibitor TNG908, designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion.
  • TNG908 has a unique MTA-cooperative binding mechanism that selectively binds the PRMT5·MTA complex, driving selective inhibition of PRMT5 in MTAP-null cancers.
  • The study aims to demonstrate the potential of TNG908 for histology-agnostic clinical development in MTAP-deleted solid tumors, including CNS malignancies, through a Phase I/II clinical trial (NCT05275478).

Comparative Analysis & Findings

  • TNG908 selectively binds the PRMT5·MTA complex, creating a large therapeutic index relative to first-generation PRMT5 inhibitors.
  • Strong preclinical activity is demonstrated in multiple MTAP-deleted xenograft models.
  • Brain penetrance is demonstrated in preclinical models, supporting the potential for treatment of CNS malignancies.

Implications and Future Directions

  • The study suggests that TNG908 has the potential to be a therapeutic agent for MTAP-deleted solid tumors, including CNS malignancies, in a histology-agnostic manner.
  • Future studies will be necessary to further evaluate the efficacy and safety of TNG908 in clinical trials.
  • The Phase I/II clinical trial (NCT05275478) will provide valuable insights into the potential of TNG908 as a treatment for MTAP-deleted tumors.
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