Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: Chemical structures of representative NSD2 inhibitors and degraders 10–16.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: The biological functions of NSD2 and underlying mechanisms.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: Overview of various cancers associated with NSD lysine methyltransferases (KMTases) dysregulation.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques: Migration, Mutagenesis, Activity Assay, Transformation Assay, Expressing, DNA Synthesis

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: Crystal structure of compound 50 (MR837) in complex with NSD2-PWWP1 domain (PDB ID: 6UE6). Hydrogen bonds formed between 50 and the key residues in the NSD2-PWWP1 domain are highlighted by red dashed lines. Compound 50 is shown as yellow sticks. Key residues ALA-270, TYR-233, TRP-236, PHE-266, and VAL-230 in the NSD2-PWWP1 domain are shown as green sticks.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: (a) SAM crystal structure in complex with NSD2-SET domain (PDB ID: 5LSU). SAM is shown as cyan sticks; (b) Crystal structure of DNA in complex with NSD2-PWWP1 domain (PDB ID: 5VC8). The key residues LYS-304, LYS-309, and LYS-312 in NSD2-PWWP1 domain that form direct electrostatic interactions with the DNA phosphate backbone are shown as cyan sticks; and (c) The structures of three NSD2 isoforms (NSD2-long, NSD2-short, and RE-IIBP) that are composed of multiple domains, including PWWP domain, PHD domain, SET domain (AWS/pre-SET, SET, and post-SET), etc.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: (a) Crystal structure of compound 51 (MRT866) in complex with NSD2-PWWP1 domain (PDB ID: 7MDN). Red dash lines highlight the hydrogen bonds between compound 51 and the key residues in NSD2-PWWP1 domain. Compound 51 is shown as yellow sticks. Key residues ALA-270, GLN-321, TYR-233, TRP-236, and PHE-266 in the NSD2-PWWP1 domain are shown as green sticks. (b) Crystal structure of compound 14 (UNC6934) in complex with NSD2-PWWP1 domain (PDB ID: 6XCG). Red dash lines highlight the hydrogen bonds formed between compound 14 and the key residues in NSD2-PWWP1 domain. Compound 14 is shown as yellow sticks. Key residues ALA-270, GLN-321, TYR-233, ARG-273, TRP-236, and PHE-266 in the NSD2-PWWP1 domain are shown as green sticks.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: Crystal structure of compound 54 in complex with NSD2-PWWP1 domain (PDB ID: 7VLN). Hydrogen bonds formed between compound 54 and the key residues in the NSD2-PWWP1 domain are highlighted by red dashed lines. Compound 54 is shown as yellow sticks. Key residues ALA-270, ASP-269, TYR-233, GLU-291, and GLU-272 in the NSD2-PWWP1 domain are shown as green sticks.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

doi: 10.1021/acs.jmedchem.3c00948

Figure Lengend Snippet: Crystal structure of compound 14 (UNC6934) in complex with NSD2-PWWP1 domain (PDB ID: 6XCG). Compound 14 is shown as green sticks, and the red dashed circle highlights the pyrimidine ring that points into the solvent-exposed region.

Article Snippet: Both NSD2 and its target gene HDAC2 were revealed to activate the NF-κB signaling pathway inducing the occurrence and progression of inflammation by promoting the release of proinflammatory cytokines.204 Meanwhile, NSD2 can modulate the envelope protein (protein E) of SARS-CoV2 via interactions with BRD4, suggesting that NSD2 may play an important role in the progression of SARS-CoV2.204 Proteolysis protein chimeras (PROTACs) targeting NSD2 degradation are being developed as valuable tools to explore the role of NSD2 in SARS-CoV2 and/or as potential therapeutic agents to treat COVID-19, a SARS-CoV2-related coronavirus disease (https://www.mitacs.ca/en/projects/development-targeted-degradation-nuclear-receptor-binding-set-domain-protein-2-nsd2).

Techniques: Solvent