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Related Concept Videos

Pharmacokinetics: Drug–Drug Interactions01:25

Pharmacokinetics: Drug–Drug Interactions

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Drug interactions occur when the pharmacological effect of one drug is altered by another substance, either enhancing or diminishing its activity. The drug whose activity is altered is known as the object drug, and the substance causing the alteration is called the agent drug or the precipitant. The net effects of these interactions are mostly undesirable, leading to decreased effectiveness or increased adverse effects. In rare cases, interactions can be beneficial, such as the enhanced...
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Bioequivalence of Drugs: Drugs with Multiple Indications01:09

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The concept of therapeutic equivalence (TE) in drugs with multiple indications is complex. A generic drug may be therapeutically equivalent to a brand-name product for one specific indication, but this doesn't necessarily mean it's equivalent for all other indications. Evidence of TE in one patient group and bioequivalence shown in healthy volunteers can support—but not confirm—TE for other indications. However, definitive proof requires individual clinical studies for each...
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FDA Approved Drugs: Changes to Approved Drugs

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Post-approval, manufacturers may modify an approved new or generic drug product. Such modifications can encompass alterations in the Active Pharmaceutical Ingredient (API), manufacturing process, formulation, batch size, manufacturing site, and container closure system (FDA Guidance for Industry, April 2004). Often, a drug product may undergo multiple changes.These modifications require careful evaluation to determine their potential impact on the drug product's identity, strength, quality,...
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Factors Influencing Drug Absorption: Drug Dissolution01:27

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The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
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Drug binding to proteins is a complex phenomenon influenced by various drug-related factors, each playing a significant role in the interaction between drugs and proteins within the body.
One crucial factor in drug-protein binding is the drug's lipophilicity or its affinity for fat. More lipophilic drugs tend to have higher binding extents. For example, highly lipophilic drugs like cloxacillin exhibit substantial protein binding, with as much as 95% of the drug binding to proteins. In...
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A drug interaction occurs when the concurrent use of another drug, food, or an external substance alters the pharmacological activity of a drug. This interaction can modify the action of the original drug, affecting its effectiveness and safety.Drug–food interactions are significant as they impact drug absorption, metabolism, and excretion. For example, grapefruit juice is a well-known disruptor of drug metabolism. It inhibits the cytochrome P450 3A4 enzyme, crucial for the metabolism of...
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A Mouse Model of the Cornea Pocket Assay for Angiogenesis Study
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Drugging an undruggable pocket on KRAS.

Dirk Kessler1, Michael Gmachl1, Andreas Mantoulidis1

  • 1Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria.

Proceedings of the National Academy of Sciences of the United States of America
|July 24, 2019
PubMed
Summary

Researchers discovered BI-2852, a novel KRAS inhibitor targeting an "undruggable" pocket. This breakthrough offers a new therapeutic strategy for KRAS-mutant cancers by blocking both active and inactive RAS forms.

Keywords:
KRASNMRfragment-based drug designoncologystructure-based drug design

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS proteins (KRAS, NRAS, HRAS) are small GTPases crucial for cell signaling.
  • Activating RAS mutations are common oncogenic drivers in human cancers, particularly KRAS.
  • Despite KRAS being a key drug target, no direct RAS-targeting therapeutics are approved.

Purpose of the Study:

  • To discover and characterize novel inhibitors targeting the KRAS protein.
  • To validate the druggability of the switch I/II pocket in KRAS.
  • To develop a chemical probe for targeting both active and inactive forms of KRAS.

Main Methods:

  • Structure-based drug design was employed to identify BI-2852.
  • BI-2852's binding affinity and mechanism of action were assessed.
  • Antiproliferative effects were evaluated in KRAS-mutant cancer cells.

Main Results:

  • BI-2852 (1) demonstrated nanomolar binding affinity to a previously inaccessible switch I/II pocket on RAS.
  • The inhibitor is mechanistically distinct from covalent KRASG12C inhibitors, targeting both active and inactive RAS forms.
  • BI-2852 inhibited downstream signaling and exhibited antiproliferative effects in KRAS-mutant cells.

Conclusions:

  • The switch I/II pocket on RAS is druggable.
  • BI-2852 represents a novel chemical probe for targeting both active and inactive RAS.
  • This discovery opens new avenues for therapeutic development against KRAS-driven cancers.