AI Article Synopsis
- TNG908 is a clinical-stage inhibitor targeting PRMT5, utilizing a unique binding mechanism that exploits the loss of the MTAP gene commonly found in various cancers.
- It specifically inhibits PRMT5 in cancer cells lacking MTAP, which occurs in 10-15% of human cancers and could lead to more effective treatments compared to earlier drugs.
- Ongoing Phase I/II trials are investigating the effectiveness of TNG908 in patients with MTAP-null tumors, including glioblastoma, suggesting a promising future for this therapy in multiple cancer types, particularly those affecting the brain.
Article 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).
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| http://dx.doi.org/10.1016/j.tranon.2024.102264 | DOI Listing |
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