Abstract 3022: ODY-CDK, a brain-penetrant, selective CDK2 inhibitor that demonstrates antitumor activity in an intracranial <i>CCNE1</i>-amplified breast tumor model

Abstract Cyclin-dependent kinase 2 (CDK2) is a member of the serine/threonine family of protein kinases that acts in complex with cyclins E1/E2 and A1/A2 to drive entry into and progression through S/G2-phases of the cell cycle. Amplification of CCNE1 or overexpression of cyclin E1 protein leads to persistent CDK2-cyclin E1 activation and phosphorylation of the retinoblastoma protein (pRb), thereby promoting uncontrolled cell cycle progression. In addition, cancer cells with loss-of-function (LoF) mutations in the retinoblastoma gene (RB1) exhibit variable levels of dependence on CDK2-cyclin A2 activity for progression through S/G2 phases of the cell cycle and have shown vulnerability to CDK2 inhibition. Brain metastases are frequently observed in cancers that harbor CCNE1 or RB1 alterations, such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC). Clinical-stage CDK2 inhibitors are not brain penetrant, and a brain-penetrant CDK2 inhibitor could provide a targeted therapeutic option for these high need patients. Here, we report on a brain-penetrant, selective CDK2 inhibitor, ODY-CDK, for the treatment of cancers with CCNE1 or RB1 genetic alterations with brain metastases or at high risk of developing them. ODY-CDK potently inhibits CDK2 (Ki = 3.1 nM) and demonstrates 40 to 180-fold selectivity over CDK1/5/6/7/9 as measured by cellular NanoBRET assays. ODY-CDK inhibits pRb in CCNE1-amplified ovarian and breast cancer cells and demonstrates antiproliferative activity in CCNE1-amplified and RB1-null ovarian, lung and breast cancer cells. In a clinically relevant human bone marrow assay, ODY-CDK is predicted to have a low risk of neutropenia that enables safe combinations with other agents. In vivo, once daily oral administration of ODY-CDK to mice with subcutaneous CCNE1-amplified HCC1569 breast or RB1 LoF NCI-H526 SCLC xenografts was well tolerated and demonstrated antitumor activity comparable to the clinical-stage CDK2 inhibitor PF-07104091. ODY-CDK treatment provoked sustained pRb inhibition in HCC1569 tumors. Pharmacokinetic evaluation of ODY-CDK demonstrated brain penetration across species with equivalent free exposure observed between cerebrospinal fluid (CSF) and plasma in dog (CSF Kpuu 0.9). To evaluate the intracranial efficacy, CCNE1-amplified HCC1569 cells were implanted into the cranium of NOG mice and tumor growth was measured by MRI. Daily oral dosing of ODY-CDK resulted in tumor regression in 8 out of 11 mice, while PF-07104091 showed modest activity with regression in only a single mouse. These data demonstrate that ODY-CDK is a selective brain-penetrant CDK2 inhibitor with differentiating intracranial antitumor activity to existing clinical-stage CDK2 inhibitors and support the evaluation of ODY-CDK in patients with brain metastases that have a high unmet medical need. Citation Format: Joe Gozgit, Gerald Lelais, Ellen Vieux, Sam Zelman, Laura Stransky, Hyeseok Shim, Kim Aardalen, Casey Landry, Arun Thottumkara, Jin Choi, Chip Lesburg, Sebastian Schneider, Chaya Stern, Elizabeth McMillan, Hanbin Lu, Caroline Ho, Nigel Waters, John Shen, Natalie Dales, Shifeng Pan, Bob Abraham, Gary D. Glick, Elaine M. Pinheiro. ODY-CDK, a brain-penetrant, selective CDK2 inhibitor that demonstrates antitumor activity in an intracranial CCNE1-amplified breast tumor model [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 3022.