Abstract C161: Identification of a reversible selective FGFR2 clinical development candidate with potency against gatekeeper and molecular brake mutations

• Published in: Molecular cancer therapeutics Vol. 22; no. 12_Supplement; p. C161
• Main Authors: Fischer, John, Bouhana, Karyn, Brizendine, Richard, Chicarelli, Mark, Fell, Brad, Fulton, Jennifer, Guarnieri, Anna, Haygood, Leyla, Jalluri, Ravi, Johnson, Amber, Koch, Keith, Koslov-Davino, Erika, Mejia, Max, Rieger, Rob, Robinson, John, Rodriguez, Mareli, Sullivan, Francis, Wang, Yang, Winski, Shannon, Wood, Silas, Zhou, Yeyun
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.TARG-23-C161

Abstract Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations.  In addition, efficacy of these agents may be reduced due to inhibition of FGFR1 and associated dose-limiting hyperphosphatemia.  To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors.  From this series, the identification of the clinical development candidate as a potent selective reversible FGFR2 inhibitor is described.  In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and efficacy in AN3 CA tumor bearing mouse models. Citation Format: John Fischer, Karyn Bouhana, Richard Brizendine, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Keith Koch, Erika Koslov-Davino, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou. Identification of a reversible selective FGFR2 clinical development candidate with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C161.