Abstract A027: First-in-class oral macrocyclic Cyclin D1-selective inhibitors demonstrate anti-tumor activity in Cyclin D1-dependent tumors

Abstract Background: D-type cyclins (D1, D2, and D3) form complexes with cyclin-dependent kinase CDK4 or CDK6 to drive cell cycle progression by phosphorylating the retinoblastoma protein (Rb) and enabling G1/S transition. Among these, Cyclin D1 is a well-established oncogene, with t(11;14) translocation occurring in mantle cell lymphoma (MCL) and amplification or overexpression occurring in HR+/HER2- breast cancer and other solid tumors. These genetic events drive tumorigenesis and therapeutic resistance while rendering tumors particularly dependent on Cyclin D1-CDK4/6 activity. Although dual CDK4/6 inhibitors have significantly improved outcomes in HR+/HER2- breast cancer, their therapeutic index is constrained by neutropenia resulting from inhibition of the Cyclin D3–CDK6 complex, a key regulator of myeloid progenitor survival. To target Cyclin D1 specifically while avoiding toxicity of targeting Cyclin D3, we leveraged our MXMO™ platform to generate passively permeable and orally bioavailable macrocycle inhibitors that selectivity disrupt the Cyclin D1-Rb interaction and demonstrate efficacy and combination potential in Cyclin D1-dependent indications. Methods: Cyclin D1 inhibitors were evaluated for disruption of the Cyclin D1-Rb interaction, inhibition of phospho-Rb, and cell anti-proliferation in Cyclin D1-dependent cancer models, including mantle cell lymphoma (MCL) with the t(11;14) translocation and HR+/HER2- breast cancer with Cyclin D1 amplification or overexpression. Selectivity in tumor cell lines vs activity in CD34+ myeloid progenitor cells was also evaluated. In-vivo efficacy and pharmacodynamic effects were assessed in a JeKo-1 xenograft MCL model. In-vivo efficacy studies in HR+/HER2- breast cancer including combinations with CDK4-selective and ER therapies in addition to combinations with BTK inhibitors in MCL are in progress. Results: Cyclin D1-selective inhibitors potently disrupted Cyclin D1–Rb binding with 10,000-fold selectivity over Cyclin D3–Rb. In JeKo-1 cells harboring Cyclin D1 t(11;14), treatment reduced phospho-Rb and induced G1 arrest. Anti-proliferative effects extended to other Cyclin D1-dependent models, including additional MCL and Cyclin D1 amplified HR+/HER2– cell lines, but not Cyclin D2- or D3-dependent lines. CD34+ myeloid progenitor assays, used as a surrogate for predicting neutrophil lineage toxicity, demonstrated a potentially wider therapeutic window compared to palbociclib. In-vivo, oral dosing yielded dose-dependent tumor growth inhibition in the JeKo-1 CDX model. Preliminary combination studies revealed enhanced activity with BTK inhibitors in MCL and with CDK4/6 and ER therapies in HR+/HER2- models. Conclusions: Cyclin D1-selective inhibitors offer a novel therapeutic approach for Cyclin D1-dependent cancers, including MCL and HR+/HER2- breast cancer, with a differentiated safety profile compared to CDK4/6 inhibitors due to lack of Cyclin D3 inhibition. Favorable oral bioavailability and preclinical efficacy support advancement into in-vivo safety studies with an IND expected in late 2026. Citation Format: Nathan Gushwa, Bernard Levin, Nik Mendoza, Roberta Sala, Andrew Bockus, Justin Shapiro, Meisam Nosrati, Jinshu Fang, Benedict Tsai, Daphne He, Ming-Hsun Ho, Li-Fen Liu, Stefan Gerhardy, Anuja Modi, Kai Yang, Jacqueline Bustamante, Gabriel Fung, Breena Walton, Nathan Dupper, Miguel Baldomero, Joshua Luna, Chinmay Bhatt, Eric Weber, Catherine E. Gleason, Sammy Metobo, James Aggen, Peadar Cremin, Pablo D. Garcia, Matthew Jacobson, Constantine Kreatsoulas, David J. Earp, Marie Evangelista. First-in-class oral macrocyclic Cyclin D1-selective inhibitors demonstrate anti-tumor activity in Cyclin D1-dependent tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A027.