Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput...

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Notch signaling is crucial for cell functions but its aberrant activation is linked to cancer.
• Current therapies indirectly inhibit Notch signaling via γ-Secretase, affecting multiple substrates.
• Jagged-mediated Notch activation is vital in cancer biology and tumor microenvironment interactions.

Purpose of the Study:

• To develop a novel strategy for directly inhibiting Notch activation by disrupting the Notch-Jagged interaction using small molecules.
• To identify potential drug candidates for cancer treatment by targeting this specific interaction.

Main Methods:

• Utilized protein::protein docking and comparative modeling to study Notch-Jagged interactions.
• Performed in silico high-throughput screening of a chemical library against the Notch2 interaction surface.
• Validated candidate compounds in vitro using gene reporter and cell viability assays.

Main Results:

• Successfully identified two small molecule candidates with distinct anti-proliferative potency and efficacy.
• Demonstrated the feasibility of directly inhibiting Notch-Jagged interactions with small molecules.
• This study represents a first step toward developing novel drugs targeting Notch signaling in cancer.

Conclusions:

• Directly inhibiting Notch-Jagged interactions with small molecules is a viable therapeutic strategy for cancer.
• The identified compounds show promise for further development into novel anti-cancer drugs.
• This work opens new avenues for targeted cancer therapy by modulating Notch signaling.