Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

Sandeep Rana; Yogesh A Sonawane; Margaret A Taylor; Smitha Kizhake; Muhammad Zahid; Amarnath Natarajan

doi:10.1016/j.bmcl.2018.10.020

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3736-3740. doi: 10.1016/j.bmcl.2018.10.020. Epub 2018 Oct 15.

Authors

Sandeep Rana¹, Yogesh A Sonawane¹, Margaret A Taylor¹, Smitha Kizhake¹, Muhammad Zahid², Amarnath Natarajan³

Affiliations

¹ Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68022, USA.
² Department of Environmental, Agricultural and Occupational Health, Omaha, NE 68022, USA.
³ Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE 68022, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68022, USA; Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68022, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, USA. Electronic address: [email protected].

Abstract

We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.

Keywords: Aminopyrazole; Cyclin dependent kinase 2; Cyclin dependent kinase 5; Growth inhibition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amination
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
Cyclin-Dependent Kinase 2 / metabolism
Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
Cyclin-Dependent Kinase 5 / metabolism
Humans
Molecular Docking Simulation
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
Cyclin-Dependent Kinase 5
CDK2 protein, human
Cyclin-Dependent Kinase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding