Discovery of Thieno[2,3- d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells

Zhaoping Pan; Xiang Li; Yujia Wang; Qinglin Jiang; Li Jiang; Min Zhang; Nan Zhang; Fengbo Wu; Bo Liu; Gu He

doi:10.1021/acs.jmedchem.9b02178

Discovery of Thieno[2,3- d]pyrimidine-Based Hydroxamic Acid Derivatives as Bromodomain-Containing Protein 4/Histone Deacetylase Dual Inhibitors Induce Autophagic Cell Death in Colorectal Carcinoma Cells

J Med Chem. 2020 Apr 9;63(7):3678-3700. doi: 10.1021/acs.jmedchem.9b02178. Epub 2020 Mar 18.

Authors

Zhaoping Pan¹, Xiang Li¹, Yujia Wang¹, Qinglin Jiang², Li Jiang², Min Zhang², Nan Zhang¹, Fengbo Wu¹, Bo Liu¹, Gu He¹

Affiliations

¹ State Key Laboratory of Biotherapy and Department of Urology, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, PR China.
² School of Pharmacy and Sichuan Province College Key Laboratory of Structure-Specific Small Molecule Drugs, Chengdu Medical College, Chengdu 610500, PR China.

PMID: 32153186
DOI: 10.1021/acs.jmedchem.9b02178

Abstract

Bromodomain-containing protein 4 (BRD4) and histone deacetylases (HDAC) are both attractive epigenetic targets in cancer and other chronic diseases. Based on the integrated fragment-based drug design, synthesis, and in vitro and in vivo evaluations, a series of novel thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives are discovered as selective BRD4-HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC₅₀ values at nanomolar levels, as well as the expression level of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal carcinoma (CRC) cells via inducing autophagic cell death. It also has a good pharmacokinetic profile in rats and oral bioavailability of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. Our results suggest that the BRD4-HDAC dual inhibition might be an attractive therapeutic strategy for CRC.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Autophagy / drug effects*
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / drug therapy*
Drug Design
Drug Screening Assays, Antitumor
Female
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylase Inhibitors / therapeutic use*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / metabolism
Hydroxamic Acids / therapeutic use*
Male
Molecular Docking Simulation
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / therapeutic use
Rats, Sprague-Dawley
Signal Transduction / drug effects
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / metabolism
Thiophenes / therapeutic use
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism
Xenograft Model Antitumor Assays
Zebrafish

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Histone Deacetylase Inhibitors
Hydroxamic Acids
Pyrimidines
Thiophenes
Transcription Factors
Histone Deacetylases