Synthesis of a Novel Pyrano[2,3-C]pyrazole Enabling PKBβ/AKT2 Inhibitory and in Vitro Anti-Glioma Activity

A series of novel pyrano[2,3-c]pyrazoles were synthesized and screened for their potential to inhibit kinases and exhibit anti-cancer activity against primary patient derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds were evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient derived glioma stem cells and exhibited potent EC₅₀ against glioblastoma cell lines. Herein we establish a novel biochemical kinase inhibitory function for a pyrano[2,3-c]pyrazole derivative and further report its anti-glioma activity in vitro for the first time.