On April 8, 2024 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported 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) (Free AACR Whitepaper) Annual Meeting (Press release, ORIC Pharmaceuticals, APR 8, 2024, View Source [SID1234641875]).

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"ORIC-944 in combination with AR inhibitors demonstrates anti-tumor activity in multiple AR-positive prostate cancer models, supporting the planned expansion of our ORIC-944 clinical program in combination with AR inhibitors in metastatic prostate cancer," said Lori Friedman, PhD, chief scientific officer. "These encouraging preclinical findings, coupled with potential best-in-class drug properties and deepened understanding of the mechanism driving synergy, fuel our optimism for advancing this program. Additionally, the unveiling of preclinical characterization of ORIC-613, a potential first- and best-in-class selective PLK4 inhibitor, marks a significant milestone in our discovery program, with preclinical data demonstrating synthetic lethality in TRIM37-high tumors."

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 (Presentation will be available on ORIC website on Tuesday, April 9, 2024 at 2:30 p.m. PT)

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