Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously

Jie Zang; Xuewu Liang; Yongxue Huang; Yuping Jia; Xiaoyang Li; Wenfang Xu; C James Chou; Yingjie Zhang

doi:10.1021/acs.jmedchem.8b00384

Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously

J Med Chem. 2018 Jun 28;61(12):5304-5322. doi: 10.1021/acs.jmedchem.8b00384. Epub 2018 Jun 7.

Authors

Jie Zang¹, Xuewu Liang¹, Yongxue Huang², Yuping Jia³, Xiaoyang Li⁴, Wenfang Xu¹, C James Chou⁴, Yingjie Zhang¹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical of Science , Shandong University , Ji'nan , Shandong 250012 , P. R. China.
² Weifang Bochuang International Biological Medicinal Institute , Weifang , Shandong 261061 , P. R. China.
³ Shandong Academy of Pharmaceutical Sciences , Ji'nan , Shandong 250101 , P. R. China.
⁴ Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy , Medical University of South Carolina , Charleston , South Carolina 29425 , United States.

PMID: 29787262
DOI: 10.1021/acs.jmedchem.8b00384

Abstract

Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one ortho-aminoanilide 6d and one hydroxamic acid 13f exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed 6d and 13f with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds 6d and 13f possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively. 6d and 13f also exhibited uncompromised multiple tyrosine kinases inhibitory activities relative to pazopanib. The intracellular dual inhibition to HDAC and VEGFR of 6d and 13f was validated by Western blot analysis. In both HUVECs tube formation assay and rat thoracic aorta rings assay, 6d and 13f showed comparable antiangiogenic potencies to pazopanib. What's more, 6d possessed desirable pharmacokinetic profiles with the oral bioavailability of 72% in SD rats and considerable in vivo antitumor efficacy in a human colorectal adenocarcinoma (HT-29) xenograft model.

Publication types

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

MeSH terms

Adenosine Triphosphate / metabolism
Administration, Intravenous
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aorta, Thoracic / drug effects
Cell Proliferation / drug effects
Drug Evaluation, Preclinical / methods
Epigenesis, Genetic / drug effects*
HT29 Cells
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Human Umbilical Vein Endothelial Cells
Humans
Indazoles
Male
Mice, Inbred BALB C
Molecular Docking Simulation
Molecular Targeted Therapy
Pyrimidines / chemistry
Rats, Sprague-Dawley
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
Sulfonamides / chemistry
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / chemistry
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Histone Deacetylase Inhibitors
Indazoles
Pyrimidines
Sulfonamides
pazopanib
Adenosine Triphosphate
KDR protein, human
Receptors, Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor Receptor-2