Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation

Haixia Su; Yi Zou; Guofeng Chen; Huixia Dou; Hang Xie; Xiaojing Yuan; Xianglei Zhang; Naixia Zhang; Minjun Li; Yechun Xu

doi:10.1021/acs.jmedchem.9b02107

Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation

J Med Chem. 2020 Apr 23;63(8):4090-4106. doi: 10.1021/acs.jmedchem.9b02107. Epub 2020 Apr 10.

Authors

Haixia Su^{1

2}, Yi Zou¹, Guofeng Chen^{1

2}, Huixia Dou¹, Hang Xie¹, Xiaojing Yuan^{1

2}, Xianglei Zhang^{1

2}, Naixia Zhang^{3

2}, Minjun Li⁴, Yechun Xu^{1

2}

Affiliations

¹ CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.

PMID: 32202425
DOI: 10.1021/acs.jmedchem.9b02107

Abstract

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.

Publication types

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

MeSH terms

3T3 Cells
Administration, Oral
Animals
Anti-Inflammatory Agents / administration & dosage*
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / metabolism*
Biphenyl Compounds / administration & dosage
Biphenyl Compounds / chemistry
Biphenyl Compounds / metabolism
Caco-2 Cells
Dose-Response Relationship, Drug
Drug Discovery / methods*
Fatty Acid-Binding Proteins / antagonists & inhibitors*
Fatty Acid-Binding Proteins / metabolism*
Humans
Inflammation / drug therapy
Inflammation / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Protein Binding / drug effects
Protein Binding / physiology
Protein Structure, Secondary
Protein Structure, Tertiary
Pyrazoles / administration & dosage
Pyrazoles / chemistry
Pyrazoles / metabolism
Treatment Outcome

Substances

2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
Anti-Inflammatory Agents
Biphenyl Compounds
FABP4 protein, human
Fatty Acid-Binding Proteins
Pyrazoles