Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model.

Abstract

We herein report the structural optimization and structure-activity relationship studies of 5-(2,3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7 H-pyrrolo[2,3- d]pyrimidin-5-yl}-2,3-dihydro-1 H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity ( KD) of 0.004 μM and an enzymatic IC50 value of 0.011 μM and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, compound 22b exhibited excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.

• Authors: Yueshan Li, Yu Xiong, Guo Zhang, Liting Zhang, Wei Yang, Jiao Yang, Luyi Huang, Zeen Qiao, Zhuang Miao, Guifeng Lin, Qiu Sun, Ting Niu, Lijuan Chen, Dawen Niu, Linli Li, Shengyong Yang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 24 Pg. 11398-11414 (12 27 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30480444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• MLKL protein, human
• Protein Kinases
• RIPK1 protein, human
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• HT29 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Lung Neoplasms (drug therapy, secondary)
• Male
• Melanoma (pathology)
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Kinases (metabolism)
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, chemistry, metabolism)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays