Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors

Tongfei Jing; Xiuqi Miao; Feng Jiang; Ming Guo; Lingyun Xing; Junlong Zhang; Daiying Zuo; Hongrui Lei; Xin Zhai

doi:10.1016/j.bmc.2018.02.023

Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors

Bioorg Med Chem. 2018 May 1;26(8):1784-1796. doi: 10.1016/j.bmc.2018.02.023. Epub 2018 Feb 21.

Authors

Tongfei Jing¹, Xiuqi Miao¹, Feng Jiang¹, Ming Guo¹, Lingyun Xing¹, Junlong Zhang¹, Daiying Zuo¹, Hongrui Lei¹, Xin Zhai²

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].

PMID: 29496411
DOI: 10.1016/j.bmc.2018.02.023

Abstract

In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC₅₀ values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 μM at 10 μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC₅₀ value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.

Keywords: ATX; EGFR; IPF-LC; Inhibitor; Semicarbazones; THPPs.

Publication types

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

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Fibroblasts / drug effects
Humans
Macrophages / drug effects
Mice
Molecular Docking Simulation
Molecular Structure
Phosphoric Diester Hydrolases / metabolism*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
RAW 264.7 Cells
Real-Time Polymerase Chain Reaction
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Antineoplastic Agents
Enzyme Inhibitors
Pyridines
Pyrimidines
tetrahydropyrido(4,3-d)pyrimidine
EGFR protein, human
ErbB Receptors
Phosphoric Diester Hydrolases
alkylglycerophosphoethanolamine phosphodiesterase