SZUH280   Click here for help

GtoPdb Ligand ID: 12356

Synonyms: compound 16e [PMID: 36516047] | SZUH-280
Compound class: Synthetic organic
Comment: SZUH280 is a PROTAC type degrader of the epigenetic regulator histone deacetylase 8 (HDAC8) protein [5]. Structurally it is a chimeric molecule containing the HDAC8 inhibitor PCI-34051 [1], linked to the cereblon (CRBN)-binding ligand pomalidomide to direct the HDAC8 protein for ubiquitination and proteasomal degradation. HDAC8 is an oncology drug target whose expression is upregulated in a range of aggressive cancers. Selective inhibtion of HDAC8 [4], or downregulation through protein degradation [2-3,6] is being widely investigated for anti-tumour potential. SZUH280 is an HDAC8 degrading tool that promotes solid tumour regression in vivo.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 11
Hydrogen bond donors 4
Rotatable bonds 15
Topological polar surface area 199.01
Molecular weight 706.25
XLogP 2.23
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES ONC(=O)c1ccc2c(c1)n(cc2)Cc1ccc(cc1)OCCOCCn1nnc(c1)CNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O
Isomeric SMILES O=C(NO)c1ccc2c(n(Cc3ccc(OCCOCCn4cc(CNc5cccc6C(=O)N(C7C(=O)NC(=O)CC7)C(=O)c56)nn4)cc3)cc2)c1
InChI InChI=1S/C36H34N8O8/c45-31-11-10-29(34(47)38-31)44-35(48)27-2-1-3-28(32(27)36(44)49)37-19-25-21-43(41-39-25)14-15-51-16-17-52-26-8-4-22(5-9-26)20-42-13-12-23-6-7-24(18-30(23)42)33(46)40-50/h1-9,12-13,18,21,29,37,50H,10-11,14-17,19-20H2,(H,40,46)(H,38,45,47)
InChI Key OCXICBCMNKOWFI-UHFFFAOYSA-N
References
1. Balasubramanian S, Ramos J, Luo W, Sirisawad M, Verner E, Buggy JJ. (2008)
A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas.
Leukemia, 22 (5): 1026-34. [PMID:18256683]
2. Chotitumnavee J, Yamashita Y, Takahashi Y, Takada Y, Iida T, Oba M, Itoh Y, Suzuki T. (2022)
Selective degradation of histone deacetylase 8 mediated by a proteolysis targeting chimera (PROTAC).
Chem Commun (Camb), 58 (29): 4635-4638. [PMID:35311871]
3. Darwish S, Ghazy E, Heimburg T, Herp D, Zeyen P, Salem-Altintas R, Ridinger J, Robaa D, Schmidtkunz K, Erdmann F et al.. (2022)
Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity.
Int J Mol Sci, 23 (14). DOI: 10.3390/ijms23147535 [PMID:35886887]
4. Fontana A, Cursaro I, Carullo G, Gemma S, Butini S, Campiani G. (2022)
A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors.
Int J Mol Sci, 23 (17). DOI: 10.3390/ijms231710014 [PMID:36077415]
5. Huang J, Zhang J, Xu W, Wu Q, Zeng R, Liu Z, Tao W, Chen Q, Wang Y, Zhu WG. (2023)
Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity.
J Med Chem, 66 (2): 1186-1209. [PMID:36516047]
6. Sun Z, Deng B, Yang Z, Mai R, Huang J, Ma Z, Chen T, Chen J. (2022)
Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8.
Eur J Med Chem, 239: 114544. [PMID:35759908]