Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design

Dezhong Ji; Lingzhi Zhang; Qihua Zhu; Ying Bai; Yaoyao Wu; Yungen Xu

doi:10.1016/j.ejmech.2018.12.040

Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design

Eur J Med Chem. 2019 Feb 15:164:334-341. doi: 10.1016/j.ejmech.2018.12.040. Epub 2018 Dec 21.

Authors

Dezhong Ji¹, Lingzhi Zhang², Qihua Zhu³, Ying Bai², Yaoyao Wu², Yungen Xu⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xyg@cpu.edu.cn.

PMID: 30605831
DOI: 10.1016/j.ejmech.2018.12.040

Abstract

Constitutive activation of MAPK (RAS/RAF/MEK/ERK) pathway is frequently observed in many tumors and thus has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Inspired by the central role of the ERK1/2 signaling cascade in cancer, we describe the scaffold-hopping generation of a series of isoindolin-1-one ERK1/2 inhibitors. Our new compounds could inhibit proliferation of KRAS and BRAF mutant cells lines at low nanomolar concentrations. Compound 22a possesses acceptable pharmacokinetic profiles and showed considerable in vivo antitumor efficacy in a HCT-116 xenograft model, providing a promising basis for further optimization towards clinical ERK1/2 inhibitors.

MeSH terms

Animals
Biological Availability
Cell Line
Drug Design
Drug Discovery*
Humans
Isoindoles / chemistry*
MAP Kinase Signaling System / drug effects
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
Mutation
Protein Kinase Inhibitors / pharmacokinetics*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins p21(ras) / genetics
Structure-Activity Relationship

Substances

Isoindol-1-one
Isoindoles
KRAS protein, human
Protein Kinase Inhibitors
BRAF protein, human
Proto-Oncogene Proteins B-raf
MAPK1 protein, human
MAPK3 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Proto-Oncogene Proteins p21(ras)