Reference Detail

Ref Type

Journal Article

PMID

(38267212)

Authors

Tyhonas JS, Arnold LD, Cox JM, Franovic A, Gardiner E, Grandinetti K, Kania R, Kanouni T, Lardy M, Li C, Martin ES, Miller N, Mohan A, Murphy EA, Perez M, Soroceanu L, Timple N, Uryu S, Womble S, Kaldor SW

Title

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of medicinal chemistry			2024 Jan 24		J Med Chem

URL

Abstract Text

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene 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	G542A	missense	unknown	FGFR2 G542A lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). G542A has been identified in the scientific literature (PMID: 38267212), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 G542A FGFR2 V564L FGFR2 amp	stomach cancer	sensitive	KIN-3248	Preclinical - Pdx	Actionable	In a preclinical study, KIN-3248 treatment inhibited tumor growth in a gastric cancer patient derived xenograft (PDX) model harboring FGFR2 V564L and G542A with FGFR2 amplification (PMID: 38267212).	38267212