Abstract 1734: RP-1664: A potent and selective PLK4 inhibitor causing tumor regressions in TRIM37-high xenograft models of solid tumors

Abstract Introduction: Polo-like kinase 4 (PLK4) is a Ser/Thr mitotic kinase crucial for centriole duplication prior to mitosis. During PLK4 inhibition centrioles are lost, however microtubules can still be nucleated from within the pericentriolar material (PCM), allowing cell division. Overexpression of the E3 ligase TRIM37, often driven by gene amplification in cancer cells, results in degradation of the PCM, rendering these cancer cells hypersensitive to PLK4 inhibition due to increased dependence on centriole duplication. TRIM37 amplification occurs at high frequency in neuroblastoma, and in several solid tumors including HER2+ and HR+/HER2- breast cancers, making PLK4 inhibition a compelling cancer drug target. Methods: The identification of RP-1664 was assisted by biochemical & cell-based target engagement assays, standard ADME and PK assays and selectivity determined by kinome profiling. Functional activity of RP-1664 was measured in cell growth assays and by monitoring PLK4 and p21 levels in cells by IHC and western blot. In vivo efficacy was evaluated in several breast and solid tumor xenograft models. Results: RP-1664 is a potent and selective PLK4 inhibitor with excellent oral bioavailability. In vitro, TRIM37 high cell lines across multiple lineages are more sensitive than non-TRIM37 amplified lines to RP-1664 mediated PLK4 inhibition, confirming the synthetic lethality phenotype. RP-1664 treated cells exhibit the expected loss of centrioles, and an accumulation of PLK4 and p21 protein, consistent with PLK4 inhibition results observed by others. In vivo, RP-1664 is highly efficacious, resulting in >80% tumor growth inhibition and sustained regressions in multiple cell and patient-derived xenograft models of breast cancer at well tolerated doses and on various schedules. PK/efficacy relationships demonstrate a steep dose response suggesting a threshold of PLK4 inhibition is required for anti-tumor activity and that efficacy correlates better with extent of drug exposure (AUC) rather than maximum blood concentration (Cmax) or duration of target inhibition. Conclusions: The highly selective, orally bioavailable PLK4 inhibitor RP-1664 demonstrates overall profound efficacy in pre-clinical in vitro and in vivo xenograft models and activation of the appropriate biomarkers indicating the expected on-target activity. These data suggest that further clinical investigation of RP-1664’s anti-tumor activity in breast and other solid tumors is warranted (NCT06232408). Citation Format: Elliot Goodfellow, Frederic Vallee, Matias Casas-Selves, Monica Bubenik, Martin Duplessis, Boubacar Sow, Catalina Suarez, Li Li, Cathy Caron, Robert Papp, Marie-Eve Leclaire, Bingcan Liu, Simon Surprenant, Philippe Mochirian, Shou Yun Yin, Parham Nejad, Joseph D. Schonhoft, Rino Stocco, Claude Godbout, Prasamit Baruah, Alexanne Bonneau-Fortin, Anne Roulston, C Gary Marshall, Michal Zimmermann, Michel Gallant, W Cameron Black, Stephen J. Morris, Marc Hyer. RP-1664: A potent and selective PLK4 inhibitor causing tumor regressions in TRIM37-high xenograft models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1734.