Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties
Zhenwei Zhang1, Shan Zhao1, Jiying Pei1
1Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Abstract:
Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.
Insights
Researchers developed a new compound, 6d, that effectively triggers apoptosis in cancer cells by activating the BAX protein. This optimized BAX trigger site activator shows improved stability and anticancer effects, offering a promising therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Direct activation of the pro-apoptotic protein BAX is a potential cancer therapy.
- BTSA1 is a known BAX trigger site activator.
Purpose of the Study:
- To structurally optimize BTSA1 into novel pyrazolone derivatives.
- To evaluate the antiproliferative and apoptosis-inducing capabilities of these derivatives.
Main Methods:
- Synthesis of pyrazolone derivatives based on BTSA1.
- In vitro assessment of antiproliferative effects and apoptosis induction.
- Mechanism of action studies involving BAX activation, mitochondrial outer membrane permeabilization (MOMP), and cytochrome c release.
- Evaluation of in vitro stability and cytochrome P450 (CYPs) profile.
Main Results:
- Compound 6d demonstrated significantly enhanced antiproliferative effects and apoptosis induction compared to BTSA1.
- 6d initiated the BAX activation cascade, leading to MOMP and cytochrome c release.
- 6d exhibited improved in vitro stability and a favorable CYPs profile over BTSA1.
Conclusions:
- Compound 6d is a potent BAX trigger site activator with enhanced efficacy and drug-like properties.
- This pyrazolone derivative represents a promising foundation for developing novel cancer therapeutics targeting BAX-expressing malignancies.
More Related Videos
11:44Cellular Membrane Affinity Chromatography Columns to Identify Specialized Plant Metabolites Interacting with Immobilized Tropomyosin Kinase Receptor B
Published on: January 19, 2022
10:19Tracking Bispecific Antibody-Induced T Cell Trafficking Using Luciferase-Transduced Human T Cells
Published on: May 12, 2023
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:31The Intrinsic Apoptotic Pathway
02:50Combination Therapies and Personalized Medicine
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...