Interest builds in a new synthetic lethality story

Though the industry’s recent synthetic lethality successes have concerned PRMT5 and USP1 inhibition, one of the best-validated targets in this area of research is Werner helicase. So claims Ideaya, one of a handful of players working on inhibitors of this enzyme.

The company has a tie-up with GSK covering this and other synthetic lethality approaches, and this week said it had selected a lead candidate to take into IND-enabling studies. 

Currently, only Roche and Novartis are evaluating this mechanism in the clinic, and no human data have yet been reported. A big test is coming soon, with initial results on Novartis’s HRO761 due at the Triple (EORTC-NCI-AACR) meeting this week.

These companies, and those following behind, are taking aim at cancers with microsatellite instability (MSI), which is caused by defects in the DNA repair system and is seen across various tumour types. Ideaya flags endometrial, colorectal and gastric cancers as of particular interest.

Werner (WRN) protein, which has a role in DNA replication and repair, is said to be essential for the survival of MSI tumours. It is therefore hoped that WRN inhibitors will hit MSI-high cells only, while sparing microsatellite-stable cells.

Checkpoint inhibitors such as Keytruda are already approved to treat MSI-high cancers, but there are no targeted options.

Synthetic lethality setback 

While WRN inhibition might be relatively early, interest has been building more broadly around synthetic lethality for some time. 

GSK and Ideaya have actually been collaborating in this area since 2020, initially focusing on MAT2A, Pol Theta and WRN projects, in a deal worth $100m up front and $20m in equity. But that tie-up has already had one setback, as just over a year ago the UK big pharma decided against taking up an option on the MAT2A inhibitor IDE397. 

Ideaya said the strategic rationale for GSK developing IDE397 “became less compelling” after GSK discontinued separate Epizyme-partnered first-generation inhibitors of PRMT5 and PRMT1, and that deal was canned before Epizyme was sold to Ipsen. Pol Theta, and clearly WRN, remain in play.

Many of the other players in WRN inhibition are small, but notably Nimbus had success outside oncology with its TYK2 inhibitor, bought by Takeda last year for $4bn.

If Novartis reports promising results at the Triple Meeting more interest could build in WRN.

Werner helicase inhibitors in development

Source: OncologyPipeline.