Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

7.7K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.7K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

8.6K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.6K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

5.5K
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...
5.5K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

5.8K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.8K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Fluctuation-driven mass-selective transport in dynamic nanopores.

Nature communications·2026
Same author

Initial Experience With Endoscopic Ultrasound-Guided Gallbladder Drainage Using Lumen-apposing Metal Stents in Extremely Elderly and Frail Patients.

DEN open·2026
Same author

Rational donor placement into a native exciton manifold: cavity-anchored dyes drive sub-picosecond energy transfer in light-harvesting complex 2.

Physical chemistry chemical physics : PCCP·2026
Same author

Molecular Crystals With Reversible Chromic Three-State Crystal-to-Crystal Transformation via the Dynamic Motion of Negatively Curved π-Frameworks.

Chemistry (Weinheim an der Bergstrasse, Germany)·2026
Same author

Beyond the Paddle-Wheel Mechanism: Hop Function Analysis of Ion Transport in Organic Ionic Plastic Crystals.

Journal of the American Chemical Society·2026
Same author

Hopping dynamics of a tracer particle confined in a fluctuating lattice.

Soft matter·2026

Related Experiment Video

Updated: Jan 7, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

8.3K

Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.

Akihiro Kondo1, Kazuhiro J Fujimoto1,2, Shin-Ichi Koda3,4

  • 1Department of Chemistry, Graduate School of Science, Nagoya University, Furocho, Chikusa, Nagoya 464-8601, Japan.

Journal of Chemical Information and Modeling
|January 2, 2026
PubMed
Summary

Third-generation EGFR inhibitors like osimertinib form covalent bonds via a proton-catalyzed mechanism. This study reveals a pseudoconcerted pathway for EGFR inhibition, offering insights for developing new cancer drugs.

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

9.2K
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

10.6K

Related Experiment Videos

Last Updated: Jan 7, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

8.3K
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

9.2K
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

10.6K

Area of Science:

  • Computational Chemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Third-generation inhibitors, such as osimertinib, target epidermal growth factor receptor tyrosine kinase (EGFR-TK) through irreversible covalent inhibition.
  • The precise mechanism of covalent bond formation between osimertinib and Cys797 in EGFR-TK is not fully understood.
  • Understanding this mechanism is crucial for designing next-generation inhibitors with improved efficacy and resistance-breaking capabilities.

Purpose of the Study:

  • To elucidate the quantum mechanical mechanism of covalent bond formation between osimertinib and EGFR.
  • To investigate the role of proton catalysis in the inhibition process.
  • To explain the preferential inhibition of the T790M mutant EGFR by osimertinib.

Main Methods:

  • Density functional theory-level quantum mechanics/molecular mechanics (QM/MM) computations were employed.
  • Gibbs energy profiles were calculated to map the reaction pathway.
  • Natural bond orbital (NBO) and electrostatic potential (ESP) analyses were performed to understand electronic effects and interactions.

Main Results:

  • A proton-catalyzed, pseudoconcerted mechanism for covalent inhibition was delineated, featuring a single transition state.
  • This mechanism involves simultaneous Cys797 deprotonation, nucleophilic attack, and protonation of osimertinib's Michael acceptor.
  • Calculations rationalized osimertinib's enhanced binding to the T790M mutant via improved electrostatic interactions with Asp855.

Conclusions:

  • The study provides a detailed mechanistic framework for EGFR covalent inhibition by osimertinib, highlighting inhibitor-derived proton catalysis.
  • The findings reveal the importance of electrostatic interactions, particularly with Asp855, in stabilizing the inhibitor-target complex.
  • These insights can guide the rational design of more potent and resistance-overcoming covalent EGFR inhibitors.