Related Experiment Video

Updated: May 31, 2025

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

7.8K

Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers

Kaikai Lyu1,2, Ying Ren3, Jie Mou3

  • 1Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Journal of Medicinal Chemistry
|January 23, 2025
PubMed

Insights

Researchers designed novel dual inhibitors targeting bromodomain and extra-terminal domain (BET) and Aurora kinase A. Compound 38 demonstrated potent anticancer activity in preclinical models, reinforcing rational drug design for kinase and bromodomain targets.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Simultaneous inhibition of bromodomain and extra-terminal domain (BET) and Aurora kinases presents a promising strategy for cancer therapy.
  • Previous research on BET-kinase dual inhibitors informed the current investigation.

Purpose of the Study:

  • To design novel dual inhibitors targeting both BET and Aurora kinase A using molecular docking.
  • To optimize and identify potent dual inhibitors with potential therapeutic applications.

Main Methods:

  • Employed molecular docking to design dual BET-Aurora kinase A inhibitors.
  • Utilized cocrystal structure of BRD4 bound to inhibitor 27 for guidance during optimization.
  • Evaluated compound affinity, antiproliferative activity, pharmacokinetic profiles, and in vivo antitumor efficacy.

Main Results:

  • A series of highly potent dual BET-Aurora kinase A inhibitors were successfully designed and obtained.
  • Compound 38 displayed strong affinity for both BRD4 and Aurora kinase A.
  • Compound 38 exhibited significant antiproliferative effects, favorable pharmacokinetics, and antitumor efficacy in renal cell and colon cancer xenograft models (TGI of 45.99% and 53.06%, respectively).

Conclusions:

  • Rational design can achieve dual inhibitors targeting specific kinases and bromodomain proteins.
  • Compound 38 represents a promising candidate for further development in cancer therapy.
  • The study validates the therapeutic potential of simultaneous BET and Aurora kinase inhibition.

More Related Videos

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

14.8K
Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

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

Published on: October 26, 2015

11.3K

Related Concept Videos

Structure-Activity Relationships and Drug Design01:28

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
493
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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...
7.4K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

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...
4.8K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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...
4.6K