fgfr4 inhibitor, composition and use in pharmaceutical preparation

Abstract

The present invention proposes a FGFR4 inhibitor with 3,4-dihydropyrimidin[4,5-d]pyrimidin-2(1H)-one as the core and a covalent structure. The embodiment gives 9 specific compounds and tested the kinase inhibitory activity of these 9 compounds, wherein the half-inhibitory concentration of LX08 to the FGFR4 kinase inhibitory activity is only 7nM, which is lower than the FIIN-2 of the active control, and has potential application prospects . In addition, by performing MALDI-TOF mass spectrometry binding experiments on the synthesized compounds, we found that compounds such as LX01, LX05, LX06, LX07, and LX08 can only covalently bind to Cys552 in FGFR4, but cannot covalently bind to Cys477 in FGFR4, while LX09 is a FGFR4 inhibitor that can covalently bind to two cysteines Cys552 and Cys477 in FGFR4.

Description

technical field [0001] Described herein are compounds, methods of making the compounds, and methods of using the compounds and compositions to inhibit tyrosine kinase activity. Background technique [0002] Fibroblast growth factor receptors (FGFR) are a family of receptor tyrosine kinases that include FGFR1, FGFR2, FGFR3, FGFR4 and 18 other high-affinity receptors for different FGF ligands. These ligand-receptor combinations regulate diverse signaling and endocrine events during human tissue development. Genetic alterations of FGFR, including mutations, fusions, and gene amplifications, can lead to activation of aberrant signaling pathways and drive cancer cell growth. Researchers have detected genetic alterations in FGFR in a variety of cancer types, including breast cancer, liver cancer, squamous non-small cell lung cancer, squamous head and neck cancer, and cholangiocarcinoma, among others. The clinical validation of FGFR as a therapeutic target has been confirmed in b...

AI Technical Summary

Problems solved by technology

Among the covalent inhibitors with high potency and selectivity for FGFR4 inhibition, BLU9931, BLU-554 and H3B-6527 all covalently bind to the Cys552 sulfhydryl group of the hinge region of FGFR4 protein, while PRN1371, FIIN-2 and TAS- 120 is covalently bound to Cys477 in the p-loop of the FGFR4 protein, and can only be covalently bound to one of the cysteine ​​residues. It has not been found that it can be covalently bound to two cysteine ​​residues in the FGFR4 protein covalently bound inhibitor

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