On April 18, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported two preclinical poster presentations at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, ORIC Pharmaceuticals, APR 18, 2023, View Source [SID1234630253]).

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"Our presentations at AACR (Free AACR Whitepaper) reflect the excellent preclinical scientific support of our development pipeline," said Lori Friedman, PhD, chief scientific officer. "Preclinical data provided insights into the comprehensive biomarker strategy for ORIC-944, our PRC2 inhibitor in Phase 1 as a monotherapy for metastatic prostate cancer. We are also pleased with the progress of our PLK4 program, with data showing that the exquisite kinase selectivity is key to synthetic lethality in tumor models with high TRIM37."

Presentation details:

ORIC-944: allosteric inhibitor of PRC2
ORIC-944 is a potent, orally bioavailable, highly selective allosteric small molecule inhibitor of PRC2, the complex which tri-methylates histone H3 lysine 27 (H3K27me3) via targeting the embryonic ectoderm development (EED) subunit, and is in early clinical development as a monotherapy for patients with metastatic prostate cancer.

Poster Presentation:

Biomarker strategy for a phase 1 study of ORIC-944, a potent and selective allosteric PRC2 inhibitor, in patients with metastatic prostate cancer

Key findings of the presentation:

Preclinical pharmacology studies in mice showed that ORIC-944 induces dose- and time-dependent H3K27me3 reduction in the skin epidermis, peripheral blood monocytes, and cell free nucleosomes in plasma, with the latter PD modulation being tumor-specific.
Putative PRC2 target genes were identified via time-dependent transcriptional and epigenetic profiling of xenograft tumor models orally dosed with ORIC-944.
These studies and corresponding assay development support the comprehensive biomarker strategy of target engagement and pharmacodynamic biomarkers implemented in the ongoing Phase 1 trial of ORIC-944 in patients with metastatic prostate cancer.
PLK4 Inhibitor Program
The PLK4 inhibitor program is a small molecule therapeutic program intended to address a mechanism of innate resistance found in a subset of breast cancers, specifically a synthetic lethal interaction of polo-like kinase 4 (PLK4) inhibition in tumors bearing a TRIM37 DNA amplification/elevation. A novel, potent, highly selective, orally bioavailable PLK4 inhibitor was selected as a development candidate in the fourth quarter of 2022.

Poster Presentation:

Selective PLK4 inhibition demonstrates synthetic lethality in TRIM37 amplified neuroblastoma and breast cancer models while less selective inhibitors do not

Key findings of the presentation:

ORIC discovered novel, potent, orally bioavailable small molecule inhibitors of PLK4 that are highly selective, including against the closely related aurora kinases and PLK1-3.
ORIC PLK4 selective inhibitors show greater potency in TRIM37 high cancer cell lines relative to low TRIM37 low cell lines, whereas no differential was observed for non-selective inhibitors.
Apoptotic cell death was observed solely in TRIM37 high cancer cells for ORIC PLK4 selective inhibitors, in contrast to non-selective inhibitors which did not show this synthetic lethality.
Using a genetically engineered PLK4 cell line variant (PLK4 G95L) that prevents compound-mediated inhibition of PLK4, selective PLK4 inhibitors lose activity in TRIM37 high G95L cells, confirming on-target cell activity, compared with non-selective inhibitors whose cell potency is not dependent on PLK4 inhibition.
PLK4 inhibition blocks trans-autophosphorylation and PLK4 protein degradation and correlates with cell viability for selective compounds, and not for non-selective inhibitors.
Together these mechanistic data confirm the potential of highly selective PLK4 inhibition as a synthetic lethal therapy for TRIM37 amplified/elevated cancers.