Related Experiment Video

Updated: Aug 20, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

9.6K

Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C

Joseph R Stephenson Clarke1, Leon R Douglas2, Patrick J Duriez3

  • 1School of Chemistry and Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.

ACS Pharmacology & Translational Science
|November 21, 2022
PubMed

Insights

Researchers developed high-affinity small molecules to stabilize the p53-Y220C oncoprotein, a key target in cancer therapy. These novel compounds show promise for reactivating tumor suppressor functions and advancing clinical evaluation for cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • The tumor suppressor protein p53 is frequently inactivated in human cancers.
  • The p53-Y220C mutant is a prevalent oncogenic form, destabilized by a unique surface pocket.
  • Reactivating p53's tumor-suppressing activity is a critical goal for anticancer therapies.

Purpose of the Study:

  • To develop high-affinity small molecules that stabilize the p53-Y220C mutant.
  • To identify novel chemical probes for potential clinical evaluation in cancer treatment.

Main Methods:

  • Structure-guided design of small molecules targeting the p53-Y220C pocket.
  • Synthesis of novel compounds and evaluation of their binding affinity and protein stabilization.
  • Confirmation of binding mode using protein X-ray crystallography.

Main Results:

  • Developed two new chemical probes with sub-micromolar binding affinity for p53-Y220C in vitro.
  • Identified JC744 with a K d of 320 nM and potent in vitro protein stabilization.
  • Established structure-activity relationships and confirmed binding modes.

Conclusions:

  • Significant advancement in the development of high-affinity ligands for the p53-Y220C mutant.
  • These findings represent a milestone towards clinical evaluation of p53-Y220C targeted therapies.
  • The developed chemical probes offer a promising avenue for reactivating tumor suppressor functions in cancer.

More Related Videos

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.3K
High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy06:38

High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy

Published on: February 7, 2019

8.8K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
6.9K
Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
18.2K
Drugs that Stabilize Microtubules01:15

Drugs that Stabilize Microtubules

Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
2.1K
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
2.0K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.5K