Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors

Wenhu Zhan; Jinxin Che; Lei Xu; Yizhe Wu; Xiaobei Hu; Yubo Zhou; Gang Cheng; Yongzhou Hu; Xiaowu Dong; Jia Li

doi:10.1016/j.ejmech.2019.07.017

Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors

Eur J Med Chem. 2019 Oct 15:180:72-85. doi: 10.1016/j.ejmech.2019.07.017. Epub 2019 Jul 7.

Authors

Wenhu Zhan¹, Jinxin Che¹, Lei Xu², Yizhe Wu¹, Xiaobei Hu², Yubo Zhou², Gang Cheng³, Yongzhou Hu¹, Xiaowu Dong⁴, Jia Li⁵

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
³ College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 311402, PR China.
⁴ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: jli@simm.ac.cn.

PMID: 31301565
DOI: 10.1016/j.ejmech.2019.07.017

Abstract

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic cancer cells and their potential of inducing apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development.

Keywords: Akt inhibitor; Antitumor; Pyrazole-thiophene derivatives.

MeSH terms

Administration, Oral
Animals
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
HCT116 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Pyrazoles / administration & dosage
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Thiophenes / administration & dosage
Thiophenes / chemistry
Thiophenes / pharmacology*
Tumor Cells, Cultured

Substances

Protein Kinase Inhibitors
Pyrazoles
Thiophenes
pyrazole
Proto-Oncogene Proteins c-akt