Design, synthesis and biological evaluation of a series of novel pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as FGFRs-dominant multi-target receptor tyrosine kinase inhibitors for the treatment of gastric cancer.

Abstract

Gastric cancer is the second most lethal cancer across the world. With the progress in therapeutic approaches, the 5-year survival rate of early gastric cancer can reach > 95%. However, the prognosis and survival time of advanced gastric cancer is still somber. Therefore, more effective targeted therapies for gastric cancer treatment are urgently needed. FGFR, VEGFR and other receptor tyrosine kinases have recently been suggested as potential targets for gastric cancer treatment. We herein report the discovery of pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as a new class of FGFRs-dominant multi-target receptor tyrosine kinase inhibitors. SAR assessment identified the most active compounds 8f and 8k, which showed excellent inhibitory activity against a variety of receptor tyrosine kinases. Moreover, 8f and 8k displayed excellent potency in the SNU-16 gastric cancer cell line. Furthermore, 8f and 8k could inhibit FGFR1 phosphorylation and downstream signaling pathways as well as induce cell apoptosis. In vivo, 8f and 8k suppress tumor growth in the SNU-16 xenograft model without inducing obvious toxicity. These findings raise the possibility that compounds 8f and 8k might serve as potential agents for the treatment of gastric cancer.

• Authors: Xiuli Wu, Zhihao Liu, Cailin Gan, Wei Wei, Qianyu Zhang, Hongyao Liu, Hanyun Que, Xingping Su, Lin Yue, Hualong He, Liang Ouyang, Tinghong Ye
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 127 Pg. 105965 (10 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 35759882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Amines
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Tyrosine
• Receptor Protein-Tyrosine Kinases

Topics

• Amines (pharmacology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation
• Humans
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases
• Stomach Neoplasms (drug therapy)
• Structure-Activity Relationship
• Tyrosine (pharmacology)