Fragment-Based Discovery and Structure-Led Optimization of MSC778, the First Potent, Selective, and Orally...

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Flap endonuclease 1 (FEN1) is a key enzyme in DNA repair pathways.
• FEN1 is a therapeutic target for BRCA-mutant cancers, but existing inhibitors have limitations.
• There is a need for novel pharmacological tools to investigate FEN1 biology.

Purpose of the Study:

• To discover and characterize novel, potent, and selective FEN1 inhibitors.
• To develop advanced pharmacological tools for FEN1-targeted cancer therapy.
• To explore the therapeutic potential of FEN1 inhibition in BRCA-deficient cancers.

Main Methods:

• Metal-chelating fragment screening.
• Structure-based drug design and optimization.
• In vitro and in vivo efficacy studies in BRCA2-deficient models.

Main Results:

• Identification of MSC778, the first potent, selective, and orally bioavailable FEN1 inhibitor.
• MSC778 selectively eliminates BRCA2-deficient cancer cells.
• MSC778 potentiates PARP inhibitor (PARPi) niraparib in vivo, inducing tumor stasis in a BRCA2 KO xenograft model.

Conclusions:

• MSC778 represents a significant advancement in FEN1-targeted cancer therapy.
• The discovery highlights the potential of targeting nucleases for cancer treatment.
• This approach offers a promising strategy for developing new therapies for BRCA-mutant cancers.