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Related Concept Videos

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Related Experiment Video

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Structure-Guided Discovery of Selective USP7 Inhibitors with In Vivo Activity.

Attila Vasas1, Lisa Ivanschitz2, Balázs Molnár1

  • 1Servier Research Institute of Medicinal Chemistry, Záhony u. 7., Budapest H-1031, Hungary.

Journal of Medicinal Chemistry
|October 23, 2024
PubMed
Summary

Researchers optimized a compound targeting ubiquitin-specific protease 7 (USP7), a key protein in cancer. The improved compound achieved high affinity, demonstrated target engagement in tumors, and showed efficacy in preclinical cancer models.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Ubiquitin-specific protease 7 (USP7) is a validated target in oncology.
  • Structure-based drug design is crucial for optimizing small molecule inhibitors.

Purpose of the Study:

  • To optimize a low-micromolar USP7 inhibitor to achieve high affinity and in vivo efficacy.
  • To explore structure-activity relationships around a poorly defined binding pocket of USP7.

Main Methods:

  • Structure-guided drug design utilizing a crystal structure of a USP7 inhibitor.
  • High-throughput screening of compound libraries to identify initial hits.
  • Systematic chemical modification and screening of substituents for improved affinity.
  • In vivo studies including target engagement, tolerability, and efficacy in xenograft models.

Main Results:

  • Optimization of one region of the inhibitor led to a significant increase in binding affinity.
  • The optimized compound achieved low-nanomolar affinity for USP7.
  • The lead compound demonstrated target engagement in tumors and was well-tolerated in mice.
  • Significant efficacy was observed in preclinical xenograft cancer models.

Conclusions:

  • Structure-guided optimization of USP7 inhibitors can yield potent and efficacious drug candidates.
  • Targeting USP7 represents a promising therapeutic strategy for various cancers.
  • The developed compound shows potential for further clinical development in oncology.