GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo
Copyright policy )GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo
AbstractAbnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC50 value of 4.14 ± 0.96, 2.77 ± 0.082, and 8.10 ± 0.15 nmol/L. It effectively overcomes FGFR1‐V561F/M and other mutantresistance in Ba/F3 stable cells (IC50:8.1–55.0 nM), and effectively inhibits the growth of Ba/F3‐FGFR1‐V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials.
- Guangzhou Institutes of Biomedicine and Health China (People's Republic of)
- Chinese Academy of Science China (People's Republic of)
- Chinese Academy of Science (中国科学院) China (People's Republic of)
- Ministry of Education of the People's Republic of China China (People's Republic of)
- Guangzhou University China (People's Republic of)
Male, V561F, Morpholines, Antineoplastic Agents, Apoptosis, Mice, SCID, Cell Line, resistance, Inhibitory Concentration 50, Mice, Animals, Humans, Phosphorylation, RC254-282, Cancer Biology, Cell Proliferation, GZD824, Phenylurea Compounds, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, G1 Phase Cell Cycle Checkpoints, FGFR1, Drug Resistance, Neoplasm, Benzamides, Mutation, Pyrazoles, Drug Screening Assays, Antitumor, Neoplasm Transplantation
Male, V561F, Morpholines, Antineoplastic Agents, Apoptosis, Mice, SCID, Cell Line, resistance, Inhibitory Concentration 50, Mice, Animals, Humans, Phosphorylation, RC254-282, Cancer Biology, Cell Proliferation, GZD824, Phenylurea Compounds, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, G1 Phase Cell Cycle Checkpoints, FGFR1, Drug Resistance, Neoplasm, Benzamides, Mutation, Pyrazoles, Drug Screening Assays, Antitumor, Neoplasm Transplantation
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