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Related Concept Videos

M-Cdk Drives Transition Into Mitosis02:15

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Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
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Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
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Updated: Sep 13, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Macrocycles for Conventionally Druggable Targets: Lessons from Macrocyclic Kinase Inhibitors.

Lauren A Viarengo-Baker1, Adrian Whitty

  • 1Relay Therapeutics, 399 Binney Street, Cambridge, Massachusetts 02139, United States.

Journal of Medicinal Chemistry
|July 31, 2025
PubMed
Summary
This summary is machine-generated.

Macrocycles offer significant advantages in drug discovery for kinases and other druggable targets. While potency effects vary, macrocyclization commonly enhances selectivity and improves pharmacokinetic properties.

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Pharmacology

Background:

  • Macrocycles are increasingly used in drug discovery, even for targets with existing acyclic ligands.
  • The synthetic complexity of macrocycles necessitates understanding their specific benefits for highly druggable targets.

Purpose of the Study:

  • To evaluate the advantages of macrocyclization for inhibitors of highly druggable kinase targets.
  • To determine the impact of macrocyclization on binding affinity, selectivity, and ADME properties.

Main Methods:

  • Comparison of closely matched acyclic and macrocyclic compound pairs.
  • Analysis of effects on kinase inhibition, selectivity, and pharmacokinetic parameters.

Main Results:

  • Macrocyclization's effect on binding affinity (potency) is variable.
  • Macrocyclization frequently leads to profound improvements in selectivity.
  • Benefits observed in membrane permeability, efflux ratio, blood-brain barrier penetrance, and metabolic stability.

Conclusions:

  • Macrocycles provide distinct advantages for certain drug discovery programs targeting kinases and other conventionally druggable targets.
  • Specific scenarios warranting a macrocyclic approach in drug discovery are identified.