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 inhibitorsProjectCompanyStatusData/commentMRTX1719Mirati TherapeuticsPhase 1/2FIH data in Cancer Discovery cited 6 responses among 18 evaluable patients at doses ≥100mg QDTNG908Tango TherapeuticsPhase 1/2PK data reported; more results promised in 2024TNG462Tango TherapeuticsPhase 1/2In dose escalation, first data possible 2023AMG 193AmgenPhase 1/2Ends Dec 2025SKL27969SK BiopharmaceuticalsPhase 1/2 Ends Sep 2024SH-3765Nanjing Sanhome PharmaceuticalPhase 1Ends Mar 2023AUR105Aurigene OncologyPhase 1Ends Dec 2025SYHX2001CSPC PharmaceuticalPhase 1Ends Jan 2026SCR-6920/ SIM0272Jiangsu Simcere PharmaceuticalPhase 1Ends Oct 2027JNJ-64619178J&JPhase 1ORR 6% among 90 evaluavle subjects; likely discontinuedGSK3326595IpsenDiscontinued in ph1Former Epizyme project, GSK deal terminated in 2022PRT811Prelude TherapeuticsDiscontinued in ph10 responses in 19 solid tumour (incl glioma) subjectsPRT543Prelude TherapeuticsDiscontinued in ph11 CR in 26 evaluable solid tumour & lymphoma subjectsPF-06939999PfizerDiscontinued in ph1NoneSource: 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.