EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor

Ahmed Elkamhawy; Ahmed H E Hassan; Sora Paik; Yong Sup Lee; Hwi-Ho Lee; Ji-Sun Shin; Kyung-Tae Lee; Eun Joo Roh

doi:10.1016/j.bioorg.2019.01.017

EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor

Bioorg Chem. 2019 May:86:112-118. doi: 10.1016/j.bioorg.2019.01.017. Epub 2019 Jan 12.

Authors

Ahmed Elkamhawy¹, Ahmed H E Hassan², Sora Paik³, Yong Sup Lee⁴, Hwi-Ho Lee⁵, Ji-Sun Shin⁵, Kyung-Tae Lee⁶, Eun Joo Roh⁷

Affiliations

¹ Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
² Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: [email protected].
³ Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
⁴ Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
⁵ Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
⁶ Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: [email protected].
⁷ Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: [email protected].

PMID: 30685642
DOI: 10.1016/j.bioorg.2019.01.017

Abstract

EGFR inhibitors are well-known as anticancer agents. Quite differently, we report our effort to develop EGFR inhibitors as anti-inflammatory agents. Pyrimidinamide EGFR inhibitors eliciting low micromolar IC₅₀ and the structurally close non-EGFR inhibitor urea analog were synthesized. Comparing their nitric oxide (NO) production inhibitory activity in peritoneal macrophages and RAW 246.7 macrophages indicated that their anti-inflammatory activity in peritoneal macrophages might be a sequence of EGFR inhibition. Further evaluations proved that compound 4d significantly and dose-dependently inhibits LPS-induced iNOS expression and IL-1β, IL-6, and TNF-α production via NF-κB inactivation in peritoneal macrophages. Compound 4d might serve as a lead compound for development of a novel class of anti-inflammatory EGFR inhibitors.

Keywords: Anti-inflammatory; Cytokines production; EGFR inhibitors; Macrophages; Nitric oxide production.

Publication types

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

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Cell Survival / drug effects
Cytokines / antagonists & inhibitors
Cytokines / biosynthesis
Dose-Response Relationship, Drug
Drug Discovery
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Inflammation / drug therapy*
Inflammation / metabolism
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Macrophages / drug effects
Macrophages / metabolism
Mice
Molecular Structure
Nitric Oxide / antagonists & inhibitors
Nitric Oxide / biosynthesis
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
RAW 264.7 Cells
Structure-Activity Relationship

Substances

Amides
Anti-Inflammatory Agents, Non-Steroidal
Benzamides
Cytokines
Lipopolysaccharides
Protein Kinase Inhibitors
Pyrimidines
Nitric Oxide
EGFR protein, human
ErbB Receptors
pyrimidine