Design, synthesis and biological evaluation of pyrazolo[3,4-b]pyridine derivatives as TRK inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Tropomyosin receptor kinases (TRKs) play a crucial role in cell proliferation and differentiation.
• Continuous activation and overexpression of TRKs are implicated in cancer development.
• Targeting TRK signaling pathways presents a therapeutic strategy for various cancers.

Purpose of the Study:

• To design and synthesize novel pyrazolo[3,4-b]pyridine derivatives as potential inhibitors of TRKA.
• To evaluate the anti-proliferative activity of synthesized compounds against cancer cell lines.
• To assess the selectivity and pharmacokinetic properties of promising drug candidates.

Main Methods:

• Scaffold hopping and computer-aided drug design were employed for compound synthesis.
• A library of 38 pyrazolo[3,4-b]pyridine derivatives was synthesized.
• In vitro assays were conducted to determine TRKA inhibition (IC50), cell proliferation inhibition, and cytochrome P450 isoform activity.

Main Results:

• Compound C03 exhibited potent TRKA inhibition with an IC50 of 56 nM.
• C03 effectively inhibited Km-12 cell line proliferation (IC50 = 0.304 μM).
• C03 demonstrated selectivity against MCF-7 and HUVEC cell lines, good plasma stability, and low CYP450 inhibition (except CYP2C9).

Conclusions:

• Compound C03, a pyrazolo[3,4-b]pyridine derivative, shows promising anti-cancer potential through TRKA inhibition.
• Its favorable selectivity and pharmacokinetic profile warrant further investigation for therapeutic development.
• This study highlights the efficacy of scaffold hopping and computational approaches in discovering novel kinase inhibitors.