Seeking a better PRMT5 inhibitor

With synthetic lethality firmly back on the drug development agenda, one approach getting increasing investor attention is PRMT5 inhibition. This is likely because, in contrast to relatively niche synthetic lethality mechanisms like WEE1 and ATR inhibition, PRMT5 could be involved in 10% of all cancers, some believe. This isn't exactly a new avenue of drug development, but the difference is that companies like Tango and Mirati are now looking at second-generation inhibitors, which bind PRMT5 only when this is complexed with MTA, a substrate for the MTAP enzyme. Mirati claimed to have discovered the first approach to targeting the PRMT5/MTA complex, with MRTX9768, but now has MRTX1719 as a clinical lead. Tango Therapeutics, which has a focus across several synthetic lethality approaches, boasts two second-generation assets. Earlier projects tended to be competitive or non-competitive inhibitors that required MTA dissociation and were not specific for MTAP gene-deleted cancers, resulting in off-tumour activity and a low therapeutic index. Clinical discontinuations of such first-generation approaches include Pfizer’s PF-06939999 and Prelude’s PRT811 and PRT543, while last year GSK canned a deal covering Epizyme’s GSK3326595, before that company was bought by Ipsen.

Clinical-stage PRMT5 inhibitors

Source: OncologyPipeline, which also reveals preclinical projects from Lilly, Jubilant Therapeutics, IngenOx, Angex and others. This table has been updated to add detail on the J&J asset.