Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia

Scientific Reports
Mattia MoriRocco Palermo

Abstract

Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although 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. Here, by functional and biological analysis of the most representative molecules of an in house library of natural products, we have designed and synthetized the chalcone-derivative 8 possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines. Structure-activity relationships were afforded for the chalcone scaffold. Short term treatments with compound 8 resulted in a dose-dependent decrease of Notch signaling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. Taken together, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as an additional therapeutic option against Notch-dependent cancers.

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Citations

Mar 13, 2018·Expert Opinion on Therapeutic Targets·Diana BellaviaSaula Checquolo
Dec 1, 2018·Journal of Cellular Physiology·Raedeh SaraeiAli Hassanzadeh
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Methods Mentioned

BETA
flow cytometry
FACS
NMR
PCR

Software Mentioned

OpenEye Python Toolkit
OpenEye Toolkits

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