Oric Pharmaceuticals presents preclinical data on ORIC-944, ORIC-613

ORIC Pharmaceuticals 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 Annual Meeting. Presentation details: ORIC-944: a potent and selective allosteric inhibitor of PRC2; Discovery of ORIC-944, a novel inhibitor of PRC2 with potential best-in-class properties for the treatment of prostate cancer; ORIC-944, a potent and selective allosteric PRC2 inhibitor with potential best-in-class properties, demonstrates combination synergy with AR pathway inhibitors in prostate cancer models. 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. ORIC-613: a potent and selective PLK4 inhibitor; ORIC-613, a potential first- and best-in-class, orally bioavailable, potent and selective PLK4 inhibitor with synthetic lethality in TRIM37 high cancer models. 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.