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Ref Type Journal Article
PMID (25169980)
Authors Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Sakata K, Sase H, Isobe T, Morikami K, Shindoh H, Mio T, Ebiike H, Taka N, Aoki Y, Ishii N
Title The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 13 11 2014 Nov 2547-58 Mol Cancer Ther
URL
Abstract Text The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F-driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations.

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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
FGFR2 V563L missense gain of function - predicted FGFR2 V563L (corresponds to V562L in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V563L is predicted to confer a gain of function to the Fgfr2 protein as indicated by increased Fgfr2 kinase activity in cell culture, and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 25169980, PMID: 31109923). Y
FGFR2 V564F missense gain of function - predicted FGFR2 V564F (also referred to as V565F from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V564F results in increased kinase activity in cell culture (PMID: 25169980) and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 V564I missense gain of function FGFR2 V564I lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V564I confers a gain of function to the Fgfr2 protein as indicated by increased Fgfr2 kinase activity (PMID: 25169980), results in FGF2-independent phosphorylation of Akt and Erk in cell culture (PMID: 29540482), and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 25169980). Y
FGFR2 V564L missense gain of function - predicted FGFR2 V564L (also referred to as V565L from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V564L results in increased Fgfr2 kinase activity in cell culture and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 25169980), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 V565F missense gain of function - predicted FGFR2 V565F (corresponds to V564F in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565F results in increased Fgfr2 kinase activity in cell culture (PMID: 25169980) and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 28034880, PMID: 31109923), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
FGFR2 V565L missense gain of function - predicted FGFR2 V565L (corresponds to V564L in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V565L has been shown to be associated with secondary resistance to FGFR inhibitors and demonstrates increased Fgfr2 kinase activity in cell culture (PMID: 25169980), and therefore, is predicted to lead to a gain of Fgfr2 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 N549K endometrial cancer sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of endometrial cancer cells harboring FGFR2 N549K mutation in culture (PMID: 25169980). 25169980
FGFR3 K650E myeloid neoplasm sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of myeloma cell lines harboring FGFR3 K650E in culture (PMID: 25169980). 25169980
FGFR2 amp breast cancer sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of breast cancer cell lines harboring FGFR2 amplification in culture (PMID: 25169980). 25169980
FGFR2 V564F Advanced Solid Tumor sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited proliferation of transformed cells over expressing FGFR2 V564F in culture and inhibited tumor growth in cell line xenograft models (PMID: 25169980). 25169980
FGFR2 amp stomach cancer sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited proliferation of FGFR-amplified gastric cancer cells in culture and inhibited tumor growth in cell line xenograft models of gastric cancer harboring FGFR2 amplification (PMID: 25169980). 25169980
FGFR3 S249C urinary bladder cancer sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited proliferation of bladder cancer cells harboring FGFR3 S249C in culture and inhibited tumor growth in FGFR3 S249C-positive bladder cancer cell line xenograft models (PMID: 25169980). 25169980
FGFR3 F386L myeloid neoplasm sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of myeloma cell lines harboring FGFR3 F386L in culture (PMID: 25169980). 25169980
FGFR2 V564F Advanced Solid Tumor resistant Fexagratinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells over expressing FGFR2 V564F were resistant to AZD4547 in culture and in cell line xenograft models (PMID: 25169980). 25169980
FGFR2 K310R FGFR2 N549K endometrial cancer sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of endometrial cancer cells harboring FGFR2 K310R and FGFR2 N549K mutations in culture (PMID: 25169980). 25169980
FGFR1 amp lung non-small cell carcinoma sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of non-small cell lung cancer cell lines harboring FGFR1 amplification in culture (PMID: 25169980). 25169980
FGFR1 amp lung small cell carcinoma sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of small cell lung cancer cell lines harboring FGFR1 amplification in culture (PMID: 25169980). 25169980
FGFR2 V564L Advanced Solid Tumor resistant Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 did not inhibit Fgfr2 phosphorylation in transformed cells over expressing FGFR2 V564L in culture (PMID: 25169980). 25169980
FGFR2 V564I Advanced Solid Tumor resistant Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 did not inhibit Fgfr2 phosphorylation in transformed cells over expressing FGFR2 V564I in culture (PMID: 25169980). 25169980
FGFR2 amp colorectal cancer sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of colorectal cancer cell lines harboring FGFR2 amplification in culture (PMID: 25169980). 25169980
FGFR3 Y373C myeloid neoplasm sensitive Zoligratinib Preclinical Actionable In a preclinical study, Debio 1347 inhibited proliferation of myeloma cell lines harboring FGFR3 Y373C in culture (PMID: 25169980). 25169980
FGFR2 S252W endometrial cancer sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited proliferation of endometrial cancer cells harboring an FGFR2 S252W mutation in culture and inhibited tumor growth in FGFR2 S252W-positive endometrial cancer cell line xenograft models (PMID: 25169980). 25169980