Introduction

About 1000 molecules of a library of natural compounds were grouped in clusters according to a chemo-informatics approach. The analysis of the results obtained from biochemical and functional tests carried out on the representative molecules of the eight most populated clusters has identified chalcone C as a new Notch inhibitor.

Technical features

Gene mutations or amplifications or post-translational modifications at Notch receptors have been directly related to development, progression, angiogenesis and poor prognosis in a large number of oncological diseases including acute T-cell lymphoblastic Leukemia (T-ALL). For this reason, new Notch signalling inhibitors with a chalconic-based chemical structure have been developed. A series of analogues derived from the chemical structure of the primary active compound (hit compound) was designed and synthesised and a compound with enhanced activity (lead compound) was developed through structure-activity relationship studies (SAR). Short-term treatments and at concentrations of the order of the micro-molar with the lead compound promote the blocking of Notch signalling and the arrest of proliferation in human cell lines of T-ALL. It is important to note that exposure to the lead compound does not significantly influence proliferation in Notch-independent cell lines. The combined analysis of “Structure-Activity-Relationships” (SAR) studies and biological-functional tests on human T-ALL cells has identified a synthetic analog, called compound 8, with inhibitory capabilities of Notch signalling and cell proliferation enhanced compared to scaffold C.

Possible Applications

• Future complementary and / or alternative therapies to conventional ones in T-ALL;
• Extensible use to all cancers, both solid and haematological;
• Extensible use to non-oncological diseases, such as vascular pathologies.

Advantages

• Efficient tissue diffusion;
• Plasma clearance;
• Reduced production costs compared to current anti-Notch therapies.