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Fragment-Based Discovery of Novel MUS81 Inhibitors

Gavin W Collie1, Ulf Börjesson2, Yunhua Chen3

  • 1R&D, AstraZeneca, Cambridge CB2 0AA, U.K.

ACS Medicinal Chemistry Letters
|July 17, 2024
PubMed

Insights

Researchers discovered new small molecule inhibitors for MUS81, an enzyme crucial in cancer survival. This research provides the first structural insights into MUS81 inhibition, aiding cancer drug development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • MUS81 is a structure-selective endonuclease involved in DNA repair processes like homologous recombination and mitosis.
  • MUS81 activity is critical for cancer cell survival, especially in tumors with impaired DNA repair.
  • Targeting MUS81 presents a promising avenue for cancer therapy, but effective small molecule inhibitors are scarce.

Purpose of the Study:

  • To discover novel small molecule inhibitors of the MUS81 endonuclease.
  • To gain structural insights into MUS81 inhibition by small molecules.
  • To facilitate the optimization of potential cancer therapeutics targeting MUS81.

Main Methods:

  • Fragment-based drug discovery approach.
  • Biochemical assays to determine inhibitor activity (sub-μM).
  • Crystallography to obtain a liganded structure of MUS81 inhibitors.

Main Results:

  • Identification of novel small molecule MUS81 inhibitors with sub-micromolar biochemical activity.
  • Development of a novel crystal system for MUS81-inhibitor complexes.
  • Generation of the first structural data illustrating small molecule inhibition of MUS81.

Conclusions:

  • Fragment-based discovery yielded potent MUS81 inhibitors.
  • The obtained crystal structures provide crucial insights for rational drug design against MUS81.
  • These findings represent a significant advancement in developing MUS81-targeted cancer therapies.

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