Abstract 3090: Discovery of XNW9015, a potent, selective, and CNS-penetrating covalent inhibitor of CDK7 with excellent in vivo antitumor activities
Authors: Hu Yonghan , Wu Dongdong , Peng Wei , Wu Zhenwei , Li Xin , Zhang Xiuchun , Li Yuanbao , Kong Liang , Wei Haiyang , Liu Xiaojun , Wu Yuchuan , Le Meijie , Qiang Jing 
Published: June 2023

Abstract
Cyclin-dependent kinase 7 (CDK7) is an upstream regulator of CDKs and serve as a component of the CDK-activated kinase (CAK) along with cyclin H and MAT1, which regulates cell cycle progression by phosphorylation of cell cycle CDKs.. CAK is also a component of transcription factor TFIIH. CDK7 can phosphorylate RNA polymerase II at active gene promoters to permit transcription. Because of its dual role in transcription and cell cycle progression, and elevated expression level in various cancer types and association with their clinical outcomes, CDK7 inhibition could be an attractive therapeutic option for many cancers with cell cycle dysregulation and aberrant control of transcriptional processes. Here we present the potency, selectivity, and in vivo efficacy of XNW9015, a potent, selective, and CNS-penetrating covalent inhibitor of CDK7. XNW9015 is covalent inhibitor with a T1/2 of 588 min in a reversibility test on CDK7. Enzymatic assays demonstrated that XNW9015 selectively inhibited CDK7 (IC50, 54 nM) over other CDKs (CDK1, CDK2, CDK9, CDK12, CDK13; IC50 &gt;10 μM). XNW9015 showed excellent activities in a variety of cancer cell lines, including triple negative breast cancer (TNBC), ovarian cancer and colon cancer. In the Palbociclib-resistant breast cancer cell line MCF-7, XNW9015 exhibited antiproliferative activity, with an IC50 of 81nM, while neither Palbociclib nor Fulvestrant can inhibit the cell viability. This suggests XNW9015 has a potential to overcome drug resistance to CDK4/6 inhibitors. XNW9015 exhibited superior rodent pharmacokinetic characteristics when compared to LY3405105 (Eli Lilly and Company, WO2019099298). XNW9015 has also shown very good brain penetration capability. We measured antitumor activity of XNW9015 in vivo with that of LY3405105 in a variety of xenograft mouse models including triple negative breast cancer and colorectal cancer. These results demonstrated that XNW9015 has superior antitumor activities to LY3405105. XNW9015 has also shown a slightly better tox profile to LY3405105 in SD rats. In summary, XNW9015 has demonstrated potent in vitro and in vivo antitumor effects, favorable pharmacokinetic and toxicological properties. XNW9015 has become a potential clinical candidate for cancer therapeutics, both as monotherapies and in combination settings.
Citation Format: Yonghan Hu, Dongdong Wu, Wei Peng, Zhenwei Wu, Xin Li, Xiuchun Zhang, Yuanbao Li, Liang Kong, Haiyang Wei, Xiaojun Liu, Yuchuan Wu, Meijie Le, Jing Qiang. Discovery of XNW9015, a potent, selective, and CNS-penetrating covalent inhibitor of CDK7 with excellent in vivo antitumor activities [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 3090.