Design, Synthesis, and Structure-Activity Relationship Study of 2-Oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as New Colony Stimulating Factor 1 Receptor (CSF1R) Kinase Inhibitors

Qiuju Xun; Zhang Zhang; Jinfeng Luo; Linjiang Tong; Minhao Huang; Zhen Wang; Jian Zou; Yingqiang Liu; Yong Xu; Hua Xie; Zheng-Chao Tu; Xiaoyun Lu; Ke Ding

doi:10.1021/acs.jmedchem.7b01612

Design, Synthesis, and Structure-Activity Relationship Study of 2-Oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as New Colony Stimulating Factor 1 Receptor (CSF1R) Kinase Inhibitors

J Med Chem. 2018 Mar 22;61(6):2353-2371. doi: 10.1021/acs.jmedchem.7b01612. Epub 2018 Mar 13.

Authors

Qiuju Xun^{1

2}, Zhang Zhang³, Jinfeng Luo¹, Linjiang Tong⁴, Minhao Huang^{1

2}, Zhen Wang¹, Jian Zou³, Yingqiang Liu^{2

4

5}, Yong Xu¹, Hua Xie⁴, Zheng-Chao Tu¹, Xiaoyun Lu³, Ke Ding^{1

3

6

7}

Affiliations

¹ State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue , Guangzhou 510530 , China.
² University of Chinese Academy of Sciences , 19 Yuquan Road , Beijing 100049 , China.
³ School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
⁴ State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
⁵ School of Life Sciences , Shanghai University , No. 99 Shangda Road , Shanghai 200444 , China.
⁶ Guangzhou City Key Laboratory of Precision Chemical Drug Development , Guangzhou 510632 , China.
⁷ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development , Ministry of Education (MOE) of People's Republic of China , Guangzhou 510632 , China.

PMID: 29499108
DOI: 10.1021/acs.jmedchem.7b01612

Abstract

Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure-activity relationship study of 2-oxo-3,4-dihydropyrimido[4,5- d]pyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC₅₀ value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Biological Availability
Cell Movement / drug effects
Drug Design
ErbB Receptors / chemistry
Macrophages / drug effects
Male
Mice
Models, Molecular
Molecular Structure
Neutrophil Infiltration / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
RAW 264.7 Cells
Rats
Rats, Sprague-Dawley
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Antineoplastic Agents
CSF1R protein, human
Protein Kinase Inhibitors
Pyrimidines
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
ErbB Receptors