Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile.

Abstract

Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.

• Authors: Tingting Jin, Lei Xu, Peipei Wang, Xiaobei Hu, Runyuan Zhang, Zhiqi Wu, Wenxin Du, Weijuan Kan, Kun Li, Chang Wang, Yubo Zhou, Jia Li, Tao Liu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 20 Pg. 15069-15090 (10 28 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34665631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Biological Availability
• Cell Line
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1 (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Development
• Humans
• Mice
• Mice, Nude
• Models, Molecular
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship