Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer

Lin Tang; Weibin Wu; Cunlong Zhang; Zhichao Shi; Dawei Chen; Xin Zhai; Yuyang Jiang

doi:10.1016/j.bioorg.2021.105026

Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer

Bioorg Chem. 2021 Sep:114:105026. doi: 10.1016/j.bioorg.2021.105026. Epub 2021 May 26.

Authors

Lin Tang¹, Weibin Wu², Cunlong Zhang², Zhichao Shi³, Dawei Chen⁴, Xin Zhai⁵, Yuyang Jiang⁶

Affiliations

¹ Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
² Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
³ Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
⁴ Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
⁵ Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: zhaixin_syphu@126.com.
⁶ Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.

PMID: 34186467
DOI: 10.1016/j.bioorg.2021.105026

Abstract

In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC₅₀ = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer.

Keywords: ADME properties; Anti-cancer; Drug design; PARP inhibitors.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / metabolism
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Male
Microsomes, Liver / metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacokinetics
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerases / metabolism
Rats
Rats, Sprague-Dawley

Substances

Antineoplastic Agents
Benzimidazoles
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
PARP2 protein, human
Parp1 protein, rat
Parp2 protein, rat
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases