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Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

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Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
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Inhibition of Cdk Activity02:34

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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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Experimental RNAi

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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
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RNA Interference01:23

RNA Interference

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RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
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Indirect-Acting Cholinergic Agonists: Mechanism of Action01:18

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Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
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Related Experiment Video

Updated: Aug 1, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement.

Cynthia V Pagba1, Amit K Gupta1, Ali K Naji2

  • 1Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030, United States.

ACS Bio & Med Chem Au
|April 27, 2023
PubMed
Summary
This summary is machine-generated.

ACA-14 is a novel small molecule that inhibits KRAS, a challenging cancer target. This compound disrupts KRAS signaling and hinders the growth of pancreatic and colon cancers with mutant KRAS.

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Last Updated: Aug 1, 2025

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS is a challenging anticancer drug target due to its difficult-to-inhibit nature.
  • Developing direct inhibitors for KRAS is crucial for advancing cancer therapy.

Purpose of the Study:

  • To introduce ACA-14 as a potential direct inhibitor of KRAS.
  • To evaluate ACA-14's binding affinity, effects on KRAS interactions, and anti-cancer activity.

Main Methods:

  • Characterization of ACA-14's binding to KRAS.
  • Assessment of ACA-14's impact on KRAS effector interactions (e.g., Raf).
  • Evaluation of ACA-14's effects on nucleotide exchange rates (intrinsic and SOS-mediated).
  • Analysis of ACA-14's inhibition of MAPK signaling in KRAS-mutant cells.
  • Assessment of ACA-14's efficacy in inhibiting the growth of pancreatic and colon cancer cells harboring mutant KRAS.

Main Results:

  • ACA-14 binds to KRAS near switch regions with low micromolar affinity.
  • ACA-14 impedes KRAS interaction with Raf.
  • ACA-14 reduces both intrinsic and SOS-mediated nucleotide exchange rates.
  • ACA-14 inhibits MAPK signaling in KRAS-mutant cells.
  • ACA-14 inhibits the growth of pancreatic and colon cancer cells with mutant KRAS.

Conclusions:

  • ACA-14 serves as a promising initial lead for developing direct KRAS inhibitors.
  • ACA-14 demonstrates potential for broad-acting inhibitors targeting multiple KRAS mutants.
  • ACA-14 depletes GTP-loaded KRAS and abrogates effector-binding ability.