ORIC Pharmaceuticals, Inc. announced two oral presentations on ORIC-944, a potent and selective allosteric inhibitor of PRC2, and presentation of a new discovery candidate, ORIC-613, an orally bioavailable, potent and selective PLK4 inhibitor, at the 2024 American Association for Cancer Research (AACR) Annual Meeting. Key findings of the presentations: Discovery of ORIC-944 was enabled through structure-based drug design and leveraged a cryptic pocket in an allosteric site in EED, a subunit of PRC2. Comprehensive profiling supports ORIC-944's best-in-class properties versus competitor PRC2 inhibitors, including PF-06821497, tazemetostat, and CPI-0209: Strong potency with 106 picomolar EC50 in biochemical binding assay Superior solubility, oral bioavailability, half-life, and CYP profile in preclinical studies.

Clinical half-life estimated at approximately 20 hours, with no sign of CYP autoinduction that is observed with first-generation PRC2 inhibitors. Results from combinations with an AR inhibitor in an in vivo prostate model shows ORIC-944 provides better activity than PF-06821497. Demonstrated that EED and EZH2 inhibitors act through the same mechanism of action, making prostate cancer cells more susceptible to AR inhibition: Transcriptional changes induced by ORIC-944 were comparable to those of EZH2 inhibitors in prostate cancer models, indicating no mechanistic distinction between molecules targeting different core subunits of PRC2.

RNA sequencing of prostate cancer models revealed that ORIC-944 increases AR signaling and luminal cell fate, thereby rendering these cells more susceptible to AR inhibition. Synergy was observed both in vitro and in vivo for ORIC-944 in combination with AR inhibitors in prostate cancer models. These results position ORIC-944 as a potential best-in-class PRC2 inhibitor for combination with AR inhibitors in patients with prostate cancer Key findings of the presentation: ORIC-613 is an orally bioavailable, potent and exquisitely selective small molecule inhibitor of PLK4, which is synthetic lethal in tumor cells with high levels of TRIM37.

ORIC-613 has superior kinome selectivity versus comparator compounds CFI-400945 and RP-1664. Preclinical assessment in cancer cell lines revealed synthetic lethality, with ORIC-613 inducing apoptotic tumor cell death specifically in TRIM37-high breast cancer and neuroblastoma cells versus TRIM37-wildtype cells. Oral dosing of ORIC-613 at 150 mg/kg QD resulted in tumor regressions and tumor growth inhibition in TRIM37-high xenograft breast tumors.

ORIC-613 retained potency in breast cancer models resistant to CDK4/6 inhibitors. These results position ORIC-613 as a potential first- and best-in-class development candidate, which has the potential to benefit patients with TRIM37-high tumors.