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Related Concept Videos

Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
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Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular...
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Treatment Resistant Cancers02:56

Treatment Resistant Cancers

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Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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Transducer Mechanism: Enzyme-Linked Receptors01:27

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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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Prodrugs01:30

Prodrugs

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Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
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Drug Discovery: Overview01:26

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Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
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Related Experiment Video

Updated: Jun 5, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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"Undruggable KRAS": druggable after all.

Adrienne D Cox1,2,3, Channing J Der1,3

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; cjder@med.unc.edu adrienne_cox@med.unc.edu.

Genes & Development
|December 5, 2024
PubMed
Summary
This summary is machine-generated.

Targeting KRAS mutations, common in lung, colorectal, and pancreatic cancers, took decades. New direct RAS inhibitors and combination therapies are emerging to overcome resistance and improve treatment for KRAS-mutant cancers.

Keywords:
CRCKRASNSCLCPDACcolorectal cancernon-small cell lung cancerpancreatic ductal adenocarcinoma

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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The RAS (Rat Sarcoma) gene family, including HRAS, KRAS, and NRAS, represents the most frequently mutated oncogene group in human cancers.
  • KRAS is the predominant RAS isoform affected by mutations, particularly in lethal cancers such as lung, colorectal, and pancreatic malignancies.
  • Despite significant research, the development of effective KRAS inhibitors faced challenges, with the first clinical approvals for KRAS-mutant lung cancer occurring after nearly 40 years.

Purpose of the Study:

  • To review historical strategies for targeting RAS oncogenes and the lessons learned from past efforts.
  • To examine the current advancements in direct RAS inhibitors, including novel therapeutic approaches.
  • To explore emerging resistance mechanisms to RAS-targeted therapies and potential combination treatment strategies.

Main Methods:

  • Literature review of historical and current anti-RAS strategies.
  • Analysis of preclinical and clinical data on direct RAS inhibitors.
  • Discussion of molecular mechanisms underlying resistance to RAS-targeted therapies.
  • Evaluation of potential combination treatments involving direct RAS inhibitors.

Main Results:

  • The development of effective KRAS inhibitors was a protracted process, highlighting the complexity of targeting these proteins.
  • Recent progress has led to the approval of the first clinically effective KRAS inhibitors, primarily for lung cancer.
  • Understanding resistance mechanisms is crucial for optimizing therapeutic outcomes.
  • Combination therapies show promise for overcoming resistance and enhancing treatment efficacy.

Conclusions:

  • Targeting KRAS mutations, while historically challenging, has seen significant breakthroughs with the advent of direct inhibitors.
  • The evolving landscape of RAS inhibitors necessitates a comprehensive understanding of resistance pathways.
  • Future therapeutic strategies will likely involve combination treatments to achieve durable responses in patients with RAS-mutant cancers.