Abstract 821: A potent CDK7 inhibitor TY-2699a suppresses palbociclib-resistant breast cancer and has the potential for combination with chemotherapy or immunotherapy in solid tumors

Introduction: Development of an effective treatment strategy for CDK4 and CDK6 inhibitors (CDK4/6i)-resistan cancers has become an urgent unmet clinical need. CDK7 is a kinase at the core of transcription and also functions in regulating cell cycle progression. Recent studies have shown that CDK7 is a potential target to overcome CDK4/6i resistance. CDK7 overexpression has been identified in pancreatic cancer. High CDK7 expression blocked apoptosis of pancreatic cancer cells induced by nab-paclitaxel combined with gemcitabine. TY-2699a is a selective CDK7 inhibitor developed by TYK Medicines, Inc. Here we report that TY-2699a demonstrated superior efficacy as well as good tolerability and safety. Results: TY-2699a was more than 80-, 66- and 86-fold more active than palbociclib in palbociclib-resistant stable cell lines of MCF7, T47D and HCC1428 cells, respectively. Consistent with the in vitro results, a 40 mg/kg dose of palbociclib almost completely failed to inhibit tumor growth in the xMCF-7/Palbo-R mouse model of breast cancer. TY-2699a at a dose of 6 mg/kg significantly inhibited tumor growth. The efficacy of CT-7001 monotherapy at a dose of 100 mg/kg was comparable to that of TY-2699a at a dose of 1 mg/kg, which only mildly inhibited tumor growth. Our efficacy data of TY-2669a provides a solid rationale for further evaluation of TY-2699a +/- fulvestrant in clinical HR+Her2- CDK4/6-resistant breast cancer patients. In addition, targeted inhibition of CDK7 not only enhanced the efficacy of paclitaxel or gemcitabine in pancreatic cancer cells, but also enhanced the in vivo efficacy of nab-paclitaxel, gemcitabine, and nab-paclitaxel in combination with gemcitabine in mouse pancreatic cancer tumor models. We initiated a phase I, multicenter, open-label study of TY-2699a administered orally to adult patients with locally advanced or metastatic solid tumors in 2023. In the single-agent dose escalation stage, TY-2699a showed better clinical safety than SY-5609 did. Most Adverse events were Grade 1 or 2. Adverse events assessed as grade 3 or 4 were a decrease in PLT, diarrhea, stomatitis, and anemia. We plan to enroll 40 subjects each cohort to evaluate the efficacy of TY-2699a combination treatment in ER+/Her2- breast cancers, pancreatic cancer, and nasopharyngeal carcinoma. In summary, TY-2699a is a highly selective and potent CDK7 kinase inhibitor, The compound has potential wider therapeutic window than multiple CDK7 inhibitors that are active in the clinical development stages. TY-2699a has shown a manageable clinical safety profile. In addition to its use as monotherapy, TY-2699a has great potential for use as a combination therapy with chemotherapy or immunotherapy. Citation Format: Shengli Dong, Apeng Liang, Shaoqing Chen, Zhengfei Guo, Jian Zhu, Huan Wang, Jing-Lan Mu, Yakun Qi, Meihua Li, Kai Wang, Hongqiang Li, Xinlong Yang, Chao Zhou, Zhiyong He, Zhengzhou, Henan Niu, Mingyu Jiang, Xiugui Chen, Jun Li, Yusheng Wu. A potent CDK7 inhibitor TY-2699a suppresses palbociclib-resistant breast cancer and has the potential for combination with chemotherapy or immunotherapy in 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 821.