Structure-Based Design and Optimization of Novel, Potent and Selective Covalent FGFR2/3 Inhibitors with a Tricyclic
Xuzhi Lu1,2, Zhaodi Tian2,3, Xueqiang Li4
1International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
Journal of Medicinal Chemistry
|June 8, 2026
Summary
Researchers developed novel covalent inhibitors targeting Fibroblast Growth Factor Receptors 2 and 3 (FGFR2/3), key drivers in many cancers. The lead compound KNT-0919 shows potent and selective inhibition, demonstrating anti-cancer effects in preclinical models.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Fibroblast Growth Factor Receptors 2 and 3 (FGFR2/3) are implicated as therapeutic targets in various human cancers.
- Targeting FGFR2/3 offers a promising strategy for cancer treatment.
Purpose of the Study:
- To discover and optimize novel covalent inhibitors of FGFR2/3.
- To evaluate the efficacy and selectivity of these inhibitors in preclinical cancer models.
Main Methods:
- Structure-based design and optimization of tricyclic pyrazolopyrimidine derivatives.
- In vitro kinase inhibition assays and cell-based proliferation assays.
- Mass spectrometry, X-ray crystallography, and in vivo xenograft studies.
Main Results:
- The lead compound KNT-0919 demonstrated potent and selective inhibition of FGFR2/3 (IC50 = 1.1 nM and 0.20 nM, respectively).
- KNT-0919 selectively suppressed FGFR2-dependent cancer cell proliferation, inhibited downstream signaling, and induced apoptosis.
- The compound exhibited favorable oral bioavailability (56%) and significant tumor growth inhibition in a gastric cancer xenograft model.
Conclusions:
- Novel tricyclic covalent FGFR2/3 inhibitors were successfully developed.
- KNT-0919 represents a promising therapeutic candidate for FGFR2/3-driven cancers.
- Further clinical investigation of KNT-0919 is warranted.
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