Reference Detail

Ref Type

Journal Article

PMID

(36698015)

Authors

Lin Q, Chen X, Qu L, Guo M, Wei H, Dai S, Jiang L, Chen Y

Title

Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Communications chemistry	5	1	2022 Aug 22	100	Commun Chem

URL

Abstract Text

Fibroblast growth factor receptor (FGFR) dysregulation is involved in a variety of tumorigenesis and development. Cholangiocarcinoma is closely related with FGFR aberrations, and pemigatinib is the first drug approved to target FGFR for the treatment of cholangiocarcinoma. Herein, we undertake biochemical and structural analysis on pemigatinib against FGFRs as well as gatekeeper mutations. The results show that pemigatinib is a potent and selective FGFR1-3 inhibitor. The extensive network of hydrogen bonds and van der Waals contacts found in the FGFR1-pemigatinib binding mode accounts for the high potency. Pemigatinib also has excellent potency against the Val-to-Ile gatekeeper mutation but less potency against the Val-to-Met/Phe gatekeeper mutation in FGFR. Taken together, the inhibitory and structural profiles exemplified by pemigatinib may help to thwart Val-to-Ile gatekeeper mutation-based resistance at earlier administration and to advance the further design and improvement for inhibitors toward FGFRs with gatekeeper mutations.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 V561M	Advanced Solid Tumor	predicted - resistant	Pemigatinib	Preclinical - Biochemical	Actionable	In a preclinical study, a cell line expressing FGFR1 V561M was resistant to Pemazyre (pemigatinib) in a kinase assay (PMID: 36698015).	36698015
FGFR2 V564F	Advanced Solid Tumor	resistant	Pemigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR2 V564F was resistant to Pemazyre (pemigatinib) in a kinase assay and in culture (PMID: 36698015).	36698015
FGFR2 V564I	Advanced Solid Tumor	predicted - sensitive	Pemigatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Pemazyre (pemigatinib) treatment inhibited activity of FGFR2 V564I in a kinase assay (PMID: 36698015).	36698015
FGFR3 V555M	Advanced Solid Tumor	resistant	Pemigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR3 V555M was resistant to Pemazyre (pemigatinib) in a kinase assay and in culture (PMID: 36698015).	36698015