Abstract 3026: ARTS-023: a potent and selective CDK4 Inhibitor demonstrating anti-tumor activity in preclinical ER+ breast cancer models

Cell cycle deregulation is a hallmark of cancer, and cyclin-dependent kinases (CDKs) play a pivotal role in driving tumor proliferation by regulating cell cycle progression. Among these, CDK4 and CDK6 are critical in promoting cell G1 to S transition. While three CDK4/6 inhibitors have been approved for treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancers, eventual relapse and severe hematological toxicities, particularly neutropenia, remain major clinical challenges. Preclinical data suggest that CDK6 dependence is predominantly associated with hematopoietic and lymphoid cell lines, whereas CDK4 dependence is enriched in breast cancer cell lines. This distinction highlights the potential of developing a next-generation CDK4-selective inhibitor to minimize hematological toxicity, allow for higher CDK4 inhibition, combination with other CDK inhibitors and improve therapeutic efficacy in ER+ breast cancer. Here we report the development and preclinical characterization of ARTS-023, an orally bioavailable CDK4 inhibitor with high selectivity over CDK6. In enzymatic assay, ARTS-023 potently inhibits the activity of CDK4/CyclinD1 complex with 50% inhibitory concentration (IC50) in the sub-nanomolar range, displaying near 60-fold selectivity against CDK6 and over 130-fold selectivity against other CDKs assessed. A very low hit rate (S (10) = 0.017, at 1uM) is observed when ARTS-023 is assessed in whole Kinome profiling, further revealing the selectivity of this compound. ARTS-023 also demonstrates potent CDK4 inhibition and selectivity against CDK6 in NanoBRET and other cellular assays. ARTS-023, at low nanomolar concentrations, inhibits Rb phosphorylation and blocks the G1/S transition, resulting in growth arrest in ER+ breast cancer cell lines. Compared to palbociclib, ARTS-023 is 32-fold more selective in inhibiting the proliferation of ER+ breast cancer cell lines over human hematopoietic stem cells, suggesting that a CDK4-selective inhibitor may have reduced cytotoxicity on hematopoietic lineages. In vivo, ARTS-023 exhibited strong anti-tumor activity as a single agent across various ER+ breast cancer xenograft models. Additionally, it demonstrated robust synergistic effects when combined with the CDK2 inhibitor AVZO-021 in both palbociclib-sensitive cell line-derived xenograft models and palbociclib-resistant patient-derived xenograft models. Taken together, these findings establish ARTS-023 as a promising next-generation CDK4-selective inhibitor, offering improved efficacy and reduced toxicity for patients with ER+ breast cancer. Furthermore, the favorable toxicity profile of ARTS-023 supports the potential combination with CDK2 inhibitors to enhance therapeutic outcomes. Citation Format: Yali Guo, Jinhong Chen, Nathan Schomer, Jiaqi Liang, Tingru Zhou, Xipan Liu, Wenheng Liang, Wei Pang, Jia Fu, Xiaobin Zhang, Dai Cheng, John Campbell, Tao Ji, Fang Li, Yaoyu Chen, Qing Sheng. ARTS-023: a potent and selective CDK4 Inhibitor demonstrating anti-tumor activity in preclinical ER+ breast cancer models [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 3026.