Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Fibroblast growth factor receptors (FGFRs) are crucial in cancer development and progression.
• Targeting FGFRs presents a promising strategy for cancer treatment.
• Previous research identified a hit compound (7r) with an indazole scaffold.

Purpose of the Study:

• To design and synthesize novel fluorine-substituted compounds to enhance the cellular activity of compound 7r.
• To explore modifications targeting the ATP binding pocket toward the solvent.
• To identify potent FGFR inhibitors with improved antiproliferative properties.

Main Methods:

• Design and synthesis of novel indazole-based compounds incorporating fluorine substituents.
• Biological evaluation of synthesized compounds for FGFR inhibitory activity.
• Assessment of antiproliferative effects on cancer cell lines (KG1 and SNU16).

Main Results:

• Compound 2a, featuring a 2,6-difluoro-3-methoxyphenyl group, exhibited potent inhibition against FGFR1 (IC50 < 4.1 nM) and FGFR2 (IC50 = 2.0 ± 0.8 nM).
• Compound 2a demonstrated significant antiproliferative activity against KG1 cells (IC50 = 25.3 ± 4.6 nM) and SNU16 cells (IC50 = 77.4 ± 6.2 nM).

Conclusions:

• The novel fluorine-substituted indazole derivative, compound 2a, is a potent inhibitor of FGFR1 and FGFR2.
• Compound 2a shows promising therapeutic potential as an antiproliferative agent against specific cancer cell lines.
• Further development of compound 2a may lead to new targeted cancer therapies.