Function-oriented synthesis of Imidazo[1,2-a]pyrazine and Imidazo[1,2-b]pyridazine derivatives as potent PI3K/mTOR dual inhibitors

Chuchu Li; Yuqiao Han; Zhengyang Wang; Yanan Yu; Chen Wang; Ziwei Ren; Yanzhi Guo; Tong Zhu; XuWen Li; Suzhen Dong; Mingliang Ma

doi:10.1016/j.ejmech.2022.115030

Function-oriented synthesis of Imidazo[1,2-a]pyrazine and Imidazo[1,2-b]pyridazine derivatives as potent PI3K/mTOR dual inhibitors

Eur J Med Chem. 2023 Feb 5:247:115030. doi: 10.1016/j.ejmech.2022.115030. Epub 2022 Dec 20.

Authors

Chuchu Li¹, Yuqiao Han², Zhengyang Wang², Yanan Yu², Chen Wang³, Ziwei Ren², Yanzhi Guo², Tong Zhu², XuWen Li⁴, Suzhen Dong⁵, Mingliang Ma⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
³ School of Mathematics, Physics and Statistics, Shanghai University of Engineering Science, Shanghai, 201620, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: xwli@simm.ac.cn.
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: szdong@brain.ecnu.edu.cn.
⁶ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China; Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai, 200062, China. Electronic address: mlma@brain.ecnu.edu.cn.

PMID: 36586298
DOI: 10.1016/j.ejmech.2022.115030

Abstract

The PI3K-Akt-mTOR signaling pathway is a highly frequently activated signal transduction pathway in human malignancies, which has been a hot target for anti-tumoral drug discovery. Based on our previous research, a function-oriented synthesis (FOS) of imidazo[1,2-a]pyrazines and imidazo[1,2-b]pyridazines was conducted, and their anticancer activities in vitro and in vivo were evaluated. Among them, compound 42 exhibited excellent dual PI3K/mTOR inhibitory activity, with IC₅₀ values on PI3Kα and mTOR of 0.06 nM and 3.12 nM, respectively, much better than our previous reported compound 15a. Furthermore, compound 42 exhibited significant in vitro and in vivo anti-tumoral activities, great kinase selectivity, low hepatotoxicity, modest plasma clearance and acceptable oral bioavailability, which is a promising PI3K/mTOR targeted anti-cancer drug candidate.

Keywords: Antitumor activity; Cancer; Hepatotoxicity; PI3K/mTOR dual inhibitors.

MeSH terms

Antineoplastic Agents*
Cell Line, Tumor
Cell Proliferation
Humans
MTOR Inhibitors
Phosphatidylinositol 3-Kinases / metabolism
Protein Kinase Inhibitors / pharmacology
Pyrazines / pharmacology
Pyridazines* / pharmacology
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
MTOR Inhibitors
MTOR protein, human
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Pyrazines
Pyridazines
TOR Serine-Threonine Kinases
imidazo(1,2-b)pyridazine
imidazo(1,2-a)pyrazine