Related Experiment Video
Updated: Jul 27, 2025
08:49
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
9.2K
Discovery of the First Potent, Selective, and
Yin Sun1, Yanli Xue1, Pengkun Sun1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, P.R. China.
Journal of Medicinal Chemistry
|June 6, 2023
Summary
Researchers developed SP27, the first selective Polo-like kinase 4 (PLK4) degrader using PROTAC technology. This novel approach shows promise for treating TRIM37-amplified breast cancer by effectively degrading PLK4 and inhibiting cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Polo-like kinase 4 (PLK4) is crucial for centriole replication and a potential therapeutic target in cancers.
- TRIM37-amplified breast cancer presents a significant therapeutic challenge requiring novel treatment strategies.
Purpose of the Study:
- To discover and characterize the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader.
- To evaluate the efficacy of the novel PLK4 PROTAC, SP27, in preclinical models of TRIM37-amplified breast cancer.
Main Methods:
- Structure-activity relationship (SAR) study focusing on linker variations for PROTAC design.
- In vitro assays to assess PLK4 degradation, cell growth inhibition, and precision-therapeutic effects.
- Pharmacokinetic (PK) studies and in vivo antitumor efficacy evaluations.
Main Results:
- SP27 identified as the first selective PLK4 PROTAC degrader.
- SP27 demonstrated superior PLK4 degradation and cell growth inhibition compared to conventional inhibitor CZS-035 in TRIM37-amplified MCF-7 cells.
- SP27 exhibited 149% bioavailability and potent in vivo antitumor activity.
Conclusions:
- SP27 represents a practical and important advancement in PLK4-targeted therapy.
- The development of SP27 opens new avenues for understanding PLK4 functions and treating TRIM37-amplified breast cancer.
Related Concept Videos
01:26Drug Discovery: Overview
8.1K
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...
8.1K
01:25Drug-Receptor Bonds
3.0K
Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
In...
3.0K
01:28Structure-Activity Relationships and Drug Design
800
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...
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...
800
01:25Dose-Response Relationship: Selectivity and Specificity
7.0K
Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and...
7.0K
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
3.1K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
3.1K
01:29Cholinergic Antagonists: Chemistry and Structure-Activity Relationship
2.3K
Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic...
2.3K