Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations

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• 作者：Han Kiat Ho ; Angie Hui Ling Yeo ; Tse Siang Kang ; Boon Tin Chua
• 刊名：Drug Discovery Today
• 出版年：January, 2014
• 年：2014
• 卷：19
• 期：1
• 页码：51-62
• 全文大小：4157 K

文摘

Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis. The high homology among FGFR1-4 and also with other kinase subfamilies creates an additional challenge in developing selective inhibitors. It orchestrates an ongoing conundrum of moderating a balance between synergism through multitargeting kinase inhibition and minimizing off-target toxicities.