The inhibition profiles of 4'‐acylpyrrole–5‐fluoroindolin‐2‐ones with a C‐3' side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases

Abstract

In this study, we reported the inhibition profiles of 4′‐acylpyrrole–5‐fluoroindolin‐2‐one 3 with a C‐3′ side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases. The pyrrole‐fused cyclohexanone moiety provided 3 with the best potency to inhibit the three kinases, and the C‐3′ side chains contributed to the different inhibition profiles of 3. Compound 3b with a C‐3′ 2‐carboxylethyl side chain showed good potency for the three kinase (IC50: 25–260 nM), and compound 3g with a N,N‐dialkyl‐2‐carbamoylethyl side chain was more active for VEGFR2 (IC50: 59 nM) and PDGFR‐β (IC50: 16 nM) than FGFR‐1 (IC50: 1.7 μM). The C‐3′ 3‐(dialkylamino)propyl side chain accomplished 3h–j as selective PDGFR‐β inhibitors (IC50: 7.8–13 nM). Compound 3b was further investigated and found potent to inhibit VEGF‐ and FGF‐dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR‐1 which could account for the different inhibition profiles of 3.

Development and Application of Indolines in Pharmaceuticals

“…For FGFR-1 inhibition, the 2-carboxyl ethyl side chain at the C-3' position (compound 4 b) would enhance the effect on FGFR-1. [17]…”