Recent preclinical research positions XL309 as a compelling new cancer drug candidate,a potent and selective inhibitor of ubiquitin-specific protease 1 (USP1). This compound introduces a novel therapeutic strategy, particularly for tumors with deficiencies in DNA repair, and is now under evaluation in a Phase 1 first-in-human trialfor BRCA1/2mutated solid tumors (including mCRPC).

USP1 plays a key role in DNA repair. This mechanism is especially important given the limitations of current treatments like PARP inhibitors. While effective in many BRCA-mutated cancers, some patients do not respond, and others develop resistance. USP1 inhibition may either synergize with PARP inhibitors or overcome such resistance entirely.

Preclinical studies have confirmed XL309’s potency and selectivity for USP1, as well as its intended biological activity. The drug increased ubiquitinated PCNA and reduced overall PCNA levels in cell models, consistent with USP1 inhibition. In both cell-derived (CDX) and patient-derived xenograft (PDX) models, XL309 demonstrated robust antitumor activity, particularly in BRCA1/2-mutant tumors. When combined with PARP inhibitors (saruparib, olaparib) or irinotecan, XL309 produced durable tumor regressions—supporting strong synergy and enhanced efficacy.

Pharmacokinetic profiling in animals revealed high oral bioavailability, low clearance, and long half-life, with human projections suggesting the feasibility of once-daily oral dosing.

Now in clinical evaluation, XL309 is being tested both as monotherapy and in combination with olaparib in patients with advanced BRCA-mutated solid tumors.

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