Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors

Jing Guo; Fan Zhao; Wenbo Yin; Mingyue Zhu; Chenzhou Hao; Yu Pang; Tianxiao Wu; Jian Wang; Dongmei Zhao; Haitao Li; Maosheng Cheng

doi:10.1016/j.ejmech.2018.05.051

Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors

Eur J Med Chem. 2018 Jul 15:155:197-209. doi: 10.1016/j.ejmech.2018.05.051. Epub 2018 Jun 1.

Authors

Jing Guo¹, Fan Zhao², Wenbo Yin¹, Mingyue Zhu¹, Chenzhou Hao¹, Yu Pang¹, Tianxiao Wu¹, Jian Wang¹, Dongmei Zhao³, Haitao Li⁴, Maosheng Cheng⁵

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China.
³ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
⁴ Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China. Electronic address: [email protected].
⁵ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].

PMID: 29886323
DOI: 10.1016/j.ejmech.2018.05.051

Abstract

We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC₅₀ = 25 nM) and cellular potency (A549 IC₅₀ = 0.58 μM, HCT116 IC₅₀ = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.

Keywords: Indolin-2-one; X-ray crystallography; p21-activated kinase 4.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Cytochrome P-450 Enzyme System / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship
p21-Activated Kinases / antagonists & inhibitors*
p21-Activated Kinases / isolation & purification
p21-Activated Kinases / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Indoles
Cytochrome P-450 Enzyme System
PAK4 protein, human
p21-Activated Kinases