Abstract 4855: Development of highly selective CDK7 inhibitor Q901 for solid tumors

Abstract

Cyclin-dependent kinase 7 (CDK7) a member of the cyclin-dependent kinase family, forms a functional CDK-activating kinase (CAK) with cyclin H and MAT1, which regulates the cell cycle by phosphorylating other CDKs. CDK7 is also a component of transcription factor II H (TFIIH) that regulates transcriptional initiation and elongation through the phosphorylation of the RNA polymerase II C-terminal domain (CTD). Inhibition of CDK7 has been reported as a potential cancer therapeutic by addressing aberrant cell cycle regulation and transcription, as these abnormalities are considered main factors for tumor progression in specific types of cancer. Q901 is a novel highly selective CDK7 inhibitor in IND enabling development stage. Q901 shows extreme selectivity by singular inhibition of CDK7 among tested kinome panel. Q901 triggers G1 cell cycle arrest in specific cancer models in vitro and in vivo. Good correlation has been demonstrated between Q901 tumor growth inhibition and target engagement of a pharmacodynamics marker in treated models, suggesting CDK7 is a main driver of tumor progression in the selected models. The Q901 data supports the continued preclinical evaluation and potential of the compound as investigational treatment for patients with multiple solid tumors. Citation Format: Donghoon Yu, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, Choa Park, Euna Jeong, Sukjoon Yoon, Kiyean Nam. Development of highly selective CDK7 inhibitor Q901 for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4855.

Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

“…S1 A ). Similar results were observed with CT7001, which is also currently being evaluated in clinical trials ( 8 , 9 , 10 , 11 , 12 ) ( Fig. S1 B ).…”

“…Given its role in the cell cycle and transcription, CDK7 is a promising therapeutic target in cancer ( 4 , 5 , 6 , 7 ). CDK7 inhibitors (CDK7is) have significant efficacy in various preclinical cancer models with limited systemic toxicity ( 8 , 9 , 10 , 11 , 12 ). Based on these results, at least five CDK7i (SY5609, SY-1365-terminated, XL02, CT7001/ICE0942, Q901) are under investigation in phase I/II clinical trials ( 3 , 12 , 13 , 14 , 15 ).…”