Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14

Fleur M Ferguson; Zainab M Doctor; Scott B Ficarro; Jarrod A Marto; Nam Doo Kim; Taebo Sim; Nathanael S Gray

doi:10.1016/j.bmcl.2019.05.024

Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14

Bioorg Med Chem Lett. 2019 Aug 1;29(15):1985-1993. doi: 10.1016/j.bmcl.2019.05.024. Epub 2019 May 23.

Authors

Fleur M Ferguson¹, Zainab M Doctor¹, Scott B Ficarro², Jarrod A Marto³, Nam Doo Kim⁴, Taebo Sim⁵, Nathanael S Gray⁶

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
² Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Daegu-Gyeongbuk Medical Innovation Foundation, Republic of Korea.
⁵ Chemical Kinomics Research Center, Korea Institute of Science and Technology, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Republic of Korea.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: nathanael_gray@dfci.harvard.edu.

Abstract

The TAIRE family of kinases are an understudied branch of the CDK kinase family, that have been implicated in a number of cancers. This manuscript describes the design, synthesis and SAR of covalent CDK14 inhibitors, culminating in identification of FMF-04-159-2, a potent, covalent CDK14 inhibitor with a TAIRE kinase biased selectivity profile.

Keywords: CDK inhibitor; CDK14; CDK15; CDK16; CDK17; CDK18; Cell cycle; Covalent kinase inhibitor; Mitosis; TAIRE kinase.

Publication types

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

MeSH terms

Cyclin-Dependent Kinases / pharmacology
Cyclin-Dependent Kinases / therapeutic use*
Humans
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / chemistry*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
CDK14 protein, human
Cyclin-Dependent Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding