Related Experiment Video

Updated: Jul 15, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

Discovery and biological evaluation of HS13 as a novel covalent ligand targeting the NSD2-PWWP1 domain

Chang Liu1, Qian Wang1, Xinhua Xie2

  • 1Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.

Bioorganic & Medicinal Chemistry
|July 13, 2026
PubMed

Insights

Researchers developed HS13, a covalent compound targeting the NSD2-PWWP1 domain. This compound inhibits cancer cell proliferation and triggers NSD2 degradation, offering a new therapeutic strategy for NSD2-driven cancers.

Area of Science:

  • Epigenetics
  • Chemical Biology
  • Cancer Therapeutics

Background:

  • The PWWP1 domain of NSD2 is crucial for its function and localization, and is implicated in cancer.
  • The C294 residue on NSD2-PWWP1 presents a viable site for covalent drug targeting.

Purpose of the Study:

  • To identify and develop covalent inhibitors targeting the NSD2-PWWP1 domain.
  • To evaluate the efficacy of novel covalent compounds in inhibiting cancer cell growth and inducing NSD2 degradation.

Main Methods:

  • Screening of a 968-compound covalent library to identify initial hits.
  • Structure-activity relationship studies and affinity-guided optimization to develop lead compounds.
  • In vitro binding assays, cell proliferation assays, apoptosis assays, and cell cycle analysis.

Main Results:

  • Identified lead compound 92-B7 and optimized it to HS13 with improved potency (Kd = 8.33 μM).
  • HS13 selectively formed a covalent bond with the C294 residue of NSD2-PWWP1.
  • HS13 inhibited U2OS cell proliferation, induced apoptosis, G2-phase cell cycle arrest, and promoted NSD2 degradation.

Conclusions:

  • HS13 is a potent covalent modulator of NSD2-PWWP1.
  • Covalent targeting of the NSD2-PWWP1 domain is a promising strategy for treating NSD2-driven cancers.
Keywords:
Aromatic cageCovalent allostericPWWP domain

More Related Videos

Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins05:08

Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins

Published on: July 8, 2025

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach10:01

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

Published on: June 23, 2026

Related Concept Videos

Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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.
Drug Discovery: Overview01:26

Drug Discovery: Overview

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...