Pyrido[2, 3-d]pyrimidin-7(8H)-ones as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors.

Abstract

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low μM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.

• Authors: Minhao Huang, Yongjun Huang, Jing Guo, Lei Yu, Yu Chang, Xiaolu Wang, Jinfeng Luo, Yanhui Huang, Zhengchao Tu, Xiaoyun Lu, Yong Xu, Zhimin Zhang, Zhang Zhang, Ke Ding
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 211 Pg. 113023 (Feb 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33248853 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Pyrimidinones
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• TTK protein, human

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Apoptosis (drug effects)
• Biological Availability
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• HCT116 Cells
• Humans
• Male
• Mice
• Mice, SCID
• Molecular Docking Simulation
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidinones (administration & dosage, chemistry, pharmacology)
• Structure-Activity Relationship