Chalcones and Chalcone-mimetic Derivatives as Notch blocking agents in T-cell acute lymphoblastic leukemia

The Notch signaling pathway is an inter-cellular communication system driving many biological processes in different tissues and in a wide spectrum of organisms. Indeed, it is considered a rationale target in the therapy of cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL).[1] Although the currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side effects, limiting their widespread therapeutic use. Since natural products have long been used as medicines for human diseases and are considered a relevant resource of lead compounds for drug discovery, an in house library of natural products and their derivatives was used as a potential source of inhibitors of the Notch signaling in T-ALL.[2] Eight representative molecules of the library were selected through a cheminformatics approach and tested in vitro. The chalcone scaffold emerged as a promising tool to inhibit Notch signalling; indeed, the synthesis of several chalcones combined with their biological evaluation highlighted the 2′,4-dihydroxy-4′-methoxychalcone (named chalcone 8) as the most potent Notch inhibitor of the series, suggesting the synergistic activity of 2′- and 4-hydroxyl groups.[2] Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were further designed and synthesized and their antiproliferative activity in KOPTK1 cells was evaluated.[3] Among them, 2’,4-dihydroxy-3-methyl-4’-methoxychalcone (compound 1) and 2,4-dimethoxyphenil-7-methoxy-1,2,3,4-tetrahydronaphtalen-2-yl-methanone (compound 18) proved to be new promising Notch-blocking agents, exhibiting cell growth reduction and inhibitory effects comparable to that of compound 8