Abstract 594: ORIC-613, a potential first- and best-in-class, orally bioavailable, potent and selective PLK4 inhibitor with synthetic lethality in TRIM37 high cancer models

Abstract

Abstract A synthetic lethal interaction between polo-like kinase 4 (PLK4) and elevated TRIM37 was discovered in breast cancer and neuroblastoma (Meitinger et al. 2020; Yeow et al. 2020). High TRIM37 renders cells dependent on PLK4, a kinase that controls centriole duplication. Amplification and copy number gains of the 17q23 amplicon, where TRIM37 resides, are common in breast cancer and neuroblastoma and associated with early relapse and poor prognosis, making PLK4 a promising new synthetic lethal target for these patients. The development candidate ORIC-613 is an orally bioavailable, potent and exquisitely selective small molecule inhibitor of PLK4, which is synthetic lethal in TRIM37 high cells. ORIC-613 is highly selective against the kinome, including against the closely related aurora and PLK families. ORIC-613 ADME/PK profile includes high cell permeability and low potential for drug-drug interactions based on CYP profiling. ORIC-613 blocked PLK4 trans-autophosphorylation of phosphodegrons, leading to stabilization of PLK4, thus directly demonstrating target engagement in cells. PLK4 protein stabilization correlated with cell viability for ORIC-613, providing a quantifiable pharmacodynamic (PD) association with antitumor activity. Cell viability assessment in cancer cell lines revealed that ORIC-613 showed greater potency in TRIM37 high versus TRIM37 low cell lines. Importantly, ORIC-613 induced significantly greater apoptosis in TRIM37 high versus low cancer cell lines as measured by caspase 3/7 assay. We confirmed that ORIC-613 activity is on-target using an engineered cell line system of PLK4 G95L, in which the leucine mutation maintains enzymatic function but blocks compound binding. In cell viability assays, ORIC-613 was potent in the parental cells and lost activity in G95L cells. Analysis of genomic data from tumors indicates that TRIM37 copy number amplification and gain is prevalent across numerous cancers. Oral dosing of ORIC-613 resulted in tumor growth inhibition and regressions in TRIM37 high xenograft breast tumors with no body weight loss. In summary, ORIC-613 is a potential first- and best-in-class development candidate, with exquisite selectivity for PLK4, which demonstrates synthetic lethality in TRIM37 high tumors and has the potential to benefit these patients. Citation Format: Kyle A. Edgar, Siobhan McRee, Gina Andretta, Chelsea Chen, Christophe Colas, Wei Fang, Wayne Kong, Jason Long, Fang Liu, Jared Moore, Aleskandr Pankov, Dan Shore, Joanne Tan, Robert Warne, Livia Ulicna, Rakesh Vekariya, Anneleen Daemen, F Romero, Melissa R. Junttila, Lori S. Friedman. ORIC-613, a potential first- and best-in-class, orally bioavailable, potent and selective PLK4 inhibitor with synthetic lethality in TRIM37 high cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 594.