Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations.
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.
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phahohk@nus.edu.sg.
Han Kiat
HK
Ho
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Angie Hui Ling
AH
Yeo
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Tse Siang
TS
Kang
Singapore Oncogenome Labratory, 61 Biopolis Drive, Singapore 138673, Singapore.
Boon Tin
BT
Chua
D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods / Q000639:trends; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor