RVU305
RVU305, a potentially best-in-class, oral, brain-penetrant MTA-cooperative PRMT5 inhibitor, currently in IND/CTA enabling studies, shows strong promise in targeting MTAP-deleted cancers. In preclinical studies, RVU305 effectively suppressed tumor growth in MTAP-null cancer models while sparing normal cells.
Its antitumor activity was supported by pharmacodynamic changes observed in tumor tissues. RVU305 also demonstrated the ability to cross the blood-brain barrier, achieving predicted therapeutic concentrations in the brains of cynomolgus monkeys.
These findings position RVU305 as a compelling therapeutic candidate for patients with MTAP-deleted cancers, including those with glioblastoma.
Key highlights
RVU305 targets cancers characterized by the deletion of the MTAP metabolic gene, found in approximately 10 to 15% of all human tumors. This deletion leads to a substantial accumulation of methylthioadenosine (MTA) within cells. At high concentrations, MTA acts as a highly selective inhibitor of the PRMT5 methyltransferase, specifically competing with its substrate, S- adenosylmethionine (SAM). In cells affected by MTAP deletion, the accumulation of MTA results in a partial inhibition of PRMT5’s methylation function.
This inhibition consequently reduces the level of symmetric dimethylation of arginine across the proteome, heightening the cells’ susceptibility to alterations in methylosome activity. RVU305 is an MTA-cooperative PRMT5 inhibitor that selectively impedes the growth of cancer cells with MTAP deletions, while sparing normal cells.
Figure: MTAP deletion leads to PRMT5 inhibition via intracellular accumulation of methylthioadenosine (MTA).
Targeting MTAP-Deleted Cancers
Key Rationale and MOA:
PRMT5 MTA-cooperative inhibitors exert synthetic lethal phenotype in MTAP-deleted cells
Best-in-class potential based on robust multiparameter optimization with a focus on selectivity, potency
- Antiproliferative activity: demonstrated in MTAP-deleted cells in vitro; high potency and efficacy in large cell line panel
- Antitumor efficacy: achieved in vivo in responder CDX models with confirmed PD biomarker (SDMA)
- Brain-penetrant: observed in cynomolgus monkey
- Favorable PK profile: demonstrated in multiple species and safety
Top Tumor Indications:
MTAP deletions occur in up to 15% of all cancers, including lung, pancreatic, DLBCL, bladder, and esophageal cancers. Notably, they are found in up to 50% of glioblastoma (GBM) cases.
Ongoing translational work, leading to a differentiated clinical strategy, will support the selection of:
- Indications/tumors
- Drug combination partners
- Patient sub-populations
Status:
Complete IND/CTA-enabling studies in 2H 2025
Preclinical Program
program
indication
discovery
PRECLINICAL
PHASE I
PHASE II
partner
program
RVU305 (MTA-cooperative PRMT5)
indication
MTAP-deleted tumors
discovery
PRECLINICAL
PHASE I
PHASE II
Contact
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