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Related Concept Videos

Combined Effects of Drugs: Synergism01:27

Combined Effects of Drugs: Synergism

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Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
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Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
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Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
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Related Experiment Video

Updated: Apr 23, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors.

Victor Hernandez-Olmos1,2, Jonathan Vincent Patzke3, Caroline E Stone3

  • 1Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.

Journal of Medicinal Chemistry
|April 22, 2026
PubMed
Summary
This summary is machine-generated.

New dual inhibitors targeting USP25 and USP28 deubiquitylases (DUBs) were developed by merging AZ1 and vismodegib structures. These potent compounds show promise as chemical probes and therapeutic candidates for diseases like cancer.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • USP25 and USP28 are deubiquitylases (DUBs) implicated in cancer and cardiac dysfunction.
  • Existing dual inhibitors of USP25/USP28 show activity in the low micromolar range.

Purpose of the Study:

  • To develop a novel class of potent dual USP25/USP28 inhibitors.
  • To merge structural features of AZ1 and vismodegib for enhanced potency and selectivity.

Main Methods:

  • Structure-based drug design incorporating features of AZ1 and vismodegib.
  • Synthesis of novel small-molecule compounds.
  • Inhibition assays across multiple orthogonal assays.
  • Selectivity profiling against other ubiquitin-specific proteases.
  • Cellular assays with a validated negative control.

Main Results:

  • Newly synthesized compounds exhibit high potency for dual USP25/USP28 inhibition.
  • Compounds demonstrate excellent selectivity over other DUBs.
  • Validated cellular activity using a suitable negative control.

Conclusions:

  • The developed compounds represent a new class of potent and selective dual USP25/USP28 inhibitors.
  • These compounds serve as advanced chemical probes for studying USP25/USP28 function.
  • The findings support further therapeutic development for diseases involving USP25/USP28 dysregulation.