8STG

Discovery and clinical validation of RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations

Summary for 8STG

• Entry DOI: 10.2210/pdb8stg/pdb
• Descriptor: Fibroblast growth factor receptor 2, N-{4-[(5P)-4-amino-5-{3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}-2-methylpropanamide (2 entities in total)
• Functional Keywords: relay inhibitor, cytosolic protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73592.69

Authors

Valverde, R.,Foster, L. (deposition date: 2023-05-10, release date: 2023-06-07, Last modification date: 2024-11-13)

Primary citation

Subbiah, V.,Sahai, V.,Maglic, D.,Bruderek, K.,Toure, B.B.,Zhao, S.,Valverde, R.,O'Hearn, P.J.,Moustakas, D.T.,Schonherr, H.,Gerami-Moayed, N.,Taylor, A.M.,Hudson, B.M.,Houde, D.J.,Pal, D.,Foster, L.,Gunaydin, H.,Ayaz, P.,Sharon, D.A.,Goyal, L.,Schram, A.M.,Kamath, S.,Sherwin, C.A.,Schmidt-Kittler, O.,Jen, K.Y.,Ricard, F.,Wolf, B.B.,Shaw, D.E.,Bergstrom, D.A.,Watters, J.,Casaletto, J.B.
RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.
Cancer Discov, 13:2012-2031, 2023

PubMed Abstract: Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting.

PubMed: 37270847
DOI: 10.1158/2159-8290.CD-23-0475

Experimental method

X-RAY DIFFRACTION (3.79 Å)