In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5981-5981
Abstract:
Cell cycle dysregulation is a hallmark of cancer and represents tremendous opportunities for clinical blockage in cancer therapy. Currently, trilaciclib, palbociclib, ribociclib, and abemaciclib that bear dual specificities against CDK4 and CDK6 have been approved for clinical usage, and more CDK4/6 targeted agents are actively under clinical evaluations, among which, TY-302, a novel CDK4/6 inhibitor being developed by TYK Medicines, is under Phase II trial (NCT04433494). To further drive the potential of pharmacological regulation of cancer cell cycle, here we report a novel CDK7 kinase inhibitor TY-2699a towards clinical investigation in 2023. CDK7 is a kinase at the core of transcription and also functions in regulating cell cycle progression. CDK7 overexpression has been identified in a wide spectrum of tumor tissues including triple negative breast cancer (TNBC), ovarian carcinoma (OC), small cell lung cancer (SCLC), and pancreatic cancer, and has been correlated to poor prognosis in the diseases. These malignant pathological profiles make CDK7 a pivotal target for the development of novel cancer therapy. Several CDK7 targeted agents, such as SY-5609 and Samuraciclib (CT7001), are under development. TYK Medicines is also committed to provide novel yet safe CDK7 kinase inhibitor. Our data show that TY-2699a potently inhibits the kinase activity of CDK7 in the form of CDK7/Cyclin H/MAT1 kinase complex (IC50 9.5 nM) with high selectivity compared to that with CDK1/Cyclin A2, CDK2/Cyclin E1, CDK4/Cyclin D1, and CDK6/Cyclin D1. The screening of a panel of cancer cell lines revealed strong anti-cell proliferation activities of TY-2699a compared to that of the reference compound, and the phenotypic findings are underscored by TY-2699a-dependent cell cycle disruption. Our data demonstrate that TY-2699a triggers G2 cell cycle arrest, and induces apoptosis in tested cancer cells (HCC70, and MDA-MB-468), but not in hTERT-immortalized normal cell (RPE-hTERT). In vivo studies show that TY-2699a confers significant efficacies in tested CDX mouse models of HCC70 (TNBC), OVCAR3 (OC), and MV-4-11(AML) in a dose-dependent manner. To further validate the anti-tumor activity of the agent, BR5010, a TNBC PDX model was employed to assess the response to TY-2699a treatment. Our data show that the efficacy of TY-2699a at 3 mg/kg, bid × 21 days was similar to that of the reference compound CT7001 at 100 mg/kg, qd × 21 days, and the efficacy of TY-2699a at 6 mg/kg, bid × 21 days was significantly better than that of CT7001 at 100 mg/kg, qd × 21 days in BR5010 mouse model. In summary, we report that TY-2699a is a highly selective and potent CDK7 kinase inhibitor with an acceptable toxicity profile within the therapeutic window. TY-2699a is planned to be advanced for clinical evaluation in 2023. # Shengli Dong and Apeng Liang contributed equally to this work. * Jun Li, Shengli Dong and Apeng Liang are the correspondent authors. Citation Format: Shengli Dong, Apeng Liang, Jian Zhu, Huan Wang, Meihua Li, Kai Wang, Rongzhen Ni, Haoyun Li, Yundi Cao, Linglin Xiao, Hongqiang Li, Yian Tu, Chao Zhou, Aishen Gong, Shuyi Xu, Hui Su, Chengshan Niu, Mingyu Jiang, Feng Xing, Xiugui Chen, Shaoqing Chen, Jun Li, Yusheng Wu. TY-2699a is a highly potent CDK7 inhibitor to abolish dysfunctional tumor cell cycle for clinical development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5981.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-5981
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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