Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor

Hefeng Zhang; Xia Peng; Yang Dai; Jingwei Shao; Yinchun Ji; Yiming Sun; Bo Liu; Xu Cheng; Jing Ai; Wenhu Duan

doi:10.1021/acs.jmedchem.0c02093

Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor

J Med Chem. 2021 Apr 8;64(7):3956-3975. doi: 10.1021/acs.jmedchem.0c02093. Epub 2021 Mar 18.

Authors

Hefeng Zhang^{1

2}, Xia Peng³, Yang Dai³, Jingwei Shao^{1

2}, Yinchun Ji³, Yiming Sun³, Bo Liu³, Xu Cheng^{3

2}, Jing Ai^{3

2}, Wenhu Duan^{1

2}

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
² University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
³ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.

PMID: 33733758
DOI: 10.1021/acs.jmedchem.0c02093

Abstract

The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Axl Receptor Tyrosine Kinase
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Humans
Male
Mice
Mice, Inbred ICR
Molecular Docking Simulation
Molecular Structure
Neoplasms / drug therapy*
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pyrimidinones / chemical synthesis
Pyrimidinones / metabolism
Pyrimidinones / therapeutic use*
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Signal Transduction / drug effects
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidinones
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase