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Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with
Kevin M Cottrell1, Kimberly J Briggs1, Douglas A Whittington1
1Tango Therapeutics, Boston, Massachusetts 02215, United States.
Abstract:
It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.
Insights
A new drug, TNG908, selectively kills cancer cells lacking the MTAP gene by targeting the PRMT5 protein. This discovery offers a promising new treatment for MTAP-deleted cancers, including those in the central nervous system.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cancer cells with homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene accumulate methylthioadenosine (MTA).
- PRMT5 (protein arginine methyltransferase 5) inhibition shows potential for selective cancer cell killing in MTAP-deleted cancers.
- Leveraging MTA accumulation is key for developing targeted PRMT5 inhibitors.
Purpose of the Study:
- To discover and characterize TNG908, a novel small molecule inhibitor targeting the PRMT5·MTA complex.
- To evaluate the selective killing of MTAP-deleted cancer cells by TNG908.
- To assess the in vivo antitumor activity and blood-brain barrier (BBB) penetration of TNG908.
Main Methods:
- Discovery of TNG908 through inhibitor screening.
- In vitro assays to determine PRMT5·MTA binding and selective cell killing.
- In vivo studies using mouse xenograft models to assess antitumor activity.
- Physicochemical property analysis for BBB penetration.
Main Results:
- TNG908 potently inhibits the PRMT5·MTA complex.
- TNG908 demonstrated a 15-fold selectivity in killing MTAP-deleted (MTAP-null) cancer cells compared to MTAP-intact (MTAP WT) cells.
- Oral administration of TNG908 showed selective antitumor activity in mouse xenograft models.
- TNG908 possesses favorable physicochemical properties for BBB penetration.
Conclusions:
- TNG908 is a potent PRMT5 inhibitor that selectively targets MTAP-deleted cancer cells.
- TNG908 exhibits promising in vivo efficacy and BBB penetration, supporting its clinical development.
- TNG908 represents a potential therapeutic strategy for both CNS and non-CNS tumors with MTAP loss.
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