Discovery of pyrrolo[2,3-d]pyrimidine derivatives as potent Axl inhibitors: Design, synthesis and biological evaluation

Dandan Xu; Deqiao Sun; Wei Wang; Xia Peng; Zhengsheng Zhan; Yinchun Ji; Yanyan Shen; Meiyu Geng; Jing Ai; Wenhu Duan

doi:10.1016/j.ejmech.2021.113497

Discovery of pyrrolo[2,3-d]pyrimidine derivatives as potent Axl inhibitors: Design, synthesis and biological evaluation

Eur J Med Chem. 2021 Aug 5:220:113497. doi: 10.1016/j.ejmech.2021.113497. Epub 2021 Apr 25.

Authors

Dandan Xu¹, Deqiao Sun², Wei Wang¹, Xia Peng³, Zhengsheng Zhan⁴, Yinchun Ji³, Yanyan Shen³, Meiyu Geng², Jing Ai⁵, Wenhu Duan⁶

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
² Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Life Science and Technology, Shanghai Tech University, 393 Middle Huaxia Road, Pudong New District, Shanghai, 201210, China.
³ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China.
⁴ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China.
⁵ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Xiangshan Branch Lane, Xihu District, Hangzhou, 330106, China. Electronic address: jai@simm.ac.cn.
⁶ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: whduan@simm.ac.cn.

PMID: 33957388
DOI: 10.1016/j.ejmech.2021.113497

Abstract

Axl has emerged as an attractive target for cancer therapy due to its strong correlation with tumor growth, metastasis, poor survival, and drug resistance. Herein, we report the design, synthesis and structure-activity relationship (SAR) investigation of a series of pyrrolo[2,3-d]pyrimidine derivatives as new Axl inhibitors. Among them, the most promising compound 13b showed high enzymatic and cellular Axl potencies. Furthermore, 13b possessed preferable pharmacokinetic properties and displayed promising therapeutic effect in BaF3/TEL-Axl xenograft tumor model. Compound 13b may serve as a lead compound for new antitumor drug discovery.

Keywords: Axl; Cancer; Inhibitor; Pyrrolo[2,3-d]pyrimidine.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Axl Receptor Tyrosine Kinase
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Male
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Pyrroles
Pyrrolo(2,3-d)pyrimidine
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase