Abstract 4425: FCN-437: A novel, potent and selective oral inhibitor of CDK4/6 for the treatment of solid tumors
Authors: Lin Shu , Zhao Xingdong , Li Tongshuang , Zhang Huajie , Tan Haohan , Wang Xianlong , Jiang Lihua , Liu Yanxin , Sun Jing , Linghu Li , Liu Qihong , Li Zhifu , Zhang Weipeng , Wang Weibo 
Published: August 2019

Abstract
Cyclin-dependent kinase-4 (CDK4) and CDK6 form a complex with D-type cyclins to phosphorylate Retinoblastoma protein (Rb), leading to a loss of repression of E2F transcription factors, which enables cell cycle progression from G1 to S phase. Loss of cell cycle control caused by aberrations in CDK/Rb signaling pathway are common in solid tumors. Inhibiting CDK4/6 blocks CDK/Rb signaling pathway, which prevents cell cycle progression through G1 restriction point, thus arresting tumor cell growth. Most of the 1st generation of CDK inhibitors lack CDK family selectivity, and thus result in greater toxicity, and poor efficacy in clinical use. The emergence of a new generation of selective CDK4/6 inhibitors, including FDA approved drugs for ER+/HER2- breast cancer (ribociclib, palbociclib and abemaciclib), has shown clinically meaningful prolongation of progression-free survival over endocrine therapy alone. However, the treatment is limited for patients with brain metastases, because the blood-brain barrier (BBB) penetration of approved CDK4/6 inhibitors are either restricted, or lack of clinical assessment. Therefore, it is urgently needed to develop novel CDK4/6 inhibitors with improved effectiveness, better BBB penetration and fewer adverse effects. Here, we developed FCN-437, a novel, selective and orally active inhibitor of CDK4/6. FCN-437 has demonstrated selective inhibitory activities against CDK4/6 over other CDKs. FCN-437 has shown broad-spectrum anti-proliferating activity on Rb+ tumor cells, derived from tissues of various solid tumors. The in vitro potency of FCN-437 is 5-fold more than ribociclib, and comparable to palbociclib. Correspondingly, in tumor xenograft models of breast cancer, colon cancer and glioma, FCN-437 dramatically inhibited tumor growth, comparable or superior to approved CDK4/6 inhibitors. FCN-437 possesses good synergetic effect in combination with letrozole or fulvestrant in vivo. FCN-437 exhibits excellent pharmacokinetic (PK) properties with improved bioavailability. In particular, FCN-437 preferentially distributes to tissues including brain compared to plasma in rats, indicating improved BBB permeability, which provides an opportunity to treat tumors that have metastasized to the brain. In non-clinical studies, FCN-437 has shown preferable safety profiles with low hERG activity and no potential cardiotoxicity. No CYP450 inducing or inhibiting effect was found in FCN-437, minimizing its potential of drug interactions. Overall, FCN-437 exhibits desired drug-like properties, enhanced efficacy, improved PK properties with BBB penetration and preferable safety profiles compared to approved CDK4/6 inhibitors. FCN-437 can be a novel and effective targeted therapy either as single agent or in combination, for patients with advanced solid tumors with brain metastases. A phase 1 clinical trial of FCN-437 has been granted approval by NMPA in 2018.
Citation Format: Shu Lin, Xingdong Zhao, Tongshuang Li, Huajie Zhang, Haohan Tan, Xianlong Wang, Lihua Jiang, Yanxin Liu, Jing Sun, Li Linghu, Qihong Liu, Zhifu Li, Weipeng Zhang, Weibo Wang. FCN-437: A novel, potent and selective oral inhibitor of CDK4/6 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4425.