Related Experiment Video
Updated: Feb 7, 2026
08:00
Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
6.6K
Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative
William Cantrell1, Yue Huang2, Antonio A Menchaca3
1Medicinal and Process Chemistry, Pharmaceutical Development and Biomaterials Department, Chemistry and Chemical Engineering Division, Southwest Research Institute, P.O. Drawer 28510, San Antonio, TX 78228, USA. william.cantrell@swri.org.
Molecules (Basel, Switzerland)
|July 25, 2018
Summary
Wortmannin, a PI3K inhibitor, is toxic. A new derivative with a leucine linker shows reduced potency but may offer a safer prostate cancer therapy approach.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Wortmannin is a potent phosphoinositide 3-kinase (PI3K) inhibitor.
- Its significant in vivo toxicity limits systemic therapeutic use.
- Developing targeted pro-drugs can mitigate systemic toxicity.
Purpose of the Study:
- To synthesize and evaluate a wortmannin derivative as a potential pro-drug.
- To assess the PI3K inhibitory activity of the wortmannin-leucine derivative in prostate cancer cells.
Main Methods:
- Synthesis of a wortmannin derivative with a leucine linker at the C20 position (Wortmannin-Leu).
- Assessment of PI3K pathway inhibition in prostate cancer cells.
- Comparison of inhibitory potency against intact wortmannin and LY294002.
Main Results:
- Wortmannin-Leu exhibited a 10-fold decrease in PI3K inhibition potency compared to intact wortmannin.
- Despite reduced potency, Wortmannin-Leu remained more potent than the competitive PI3K inhibitor LY294002.
- The wortmannin derivative demonstrated PI3K pathway inhibition in prostate cancer cells.
Conclusions:
- The C20-leucine modification reduces wortmannin's PI3K inhibitory potency.
- This wortmannin derivative shows potential as a less toxic alternative for PI3K inhibition in prostate cancer.
- Further research into targeted activation of wortmannin pro-drugs is warranted.
Related Concept Videos
02:34Inhibition of Cdk Activity
6.0K
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...
6.0K
02:54Protein Kinases and Phosphatases
15.2K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
15.2K
02:54Protein Kinases and Phosphatases
4.5K
4.5K
00:46Feedback Inhibition
57.2K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.2K
02:42Eukaryotic Transcription Activators
12.8K
Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
12.8K
01:26Receptor Tyrosine Kinases
18.9K
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
18.9K