MS8815   Click here for help

GtoPdb Ligand ID: 12138

Synonyms: compound 16 [PMID: 35837138] | MS-8815
Compound class: Synthetic organic
Comment: MS8815 is a bifunctional PROTAC molecule that targets the enhancer of zeste homolog 2 (EZH2) protein for degradation [1]. It contains a VHL-binding ligand VHL-1 (a.k.a. VH032 [3]; PubChem CID 77232228; Kd 188 nM) to recruit the VHL E3 ligase, and the EZH2 engager is the FDA-approved drug tazemetostat (EPZ-6438). EZH2 overexpression is a marker of poor prognosis in triple-negative breast cancer (TNBC). Protein degrading agents are proposed as alternatives to small molecule inhibitors, and are of particular use for 'difficult-to-drug' protein targets.
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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 15
Hydrogen bond donors 5
Rotatable bonds 29
Topological polar surface area 237.85
Molecular weight 1153.64
XLogP 9.07
No. Lipinski's rules broken 3
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 CCN(c1cc(cc(c1C)C(=O)NCc1c(C)cc([nH]c1=O)C)c1ccc(cc1)CN1CCN(CC1)C(=O)CCCCCCCC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)NCc1ccc(cc1)c1scnc1C)O)C1CCOCC1
Isomeric SMILES Cc1c(c(=O)[nH]c(c1)C)CNC(=O)c1cc(cc(c1C)N(C1CCOCC1)CC)c1ccc(cc1)CN1CCN(CC1)C(=O)CCCCCCCC(=O)N[C@H](C(=O)N1[C@@H](C[C@H](C1)O)C(=O)NCc1ccc(cc1)c1c(ncs1)C)C(C)(C)C
InChI InChI=1S/C65H87N9O8S/c1-9-73(51-25-31-82-32-26-51)55-35-50(34-53(44(55)4)61(78)67-38-54-42(2)33-43(3)69-62(54)79)48-21-19-47(20-22-48)39-71-27-29-72(30-28-71)58(77)16-14-12-10-11-13-15-57(76)70-60(65(6,7)8)64(81)74-40-52(75)36-56(74)63(80)66-37-46-17-23-49(24-18-46)59-45(5)68-41-83-59/h17-24,33-35,41,51-52,56,60,75H,9-16,25-32,36-40H2,1-8H3,(H,66,80)(H,67,78)(H,69,79)(H,70,76)/t52-,56+,60-/m1/s1
InChI Key AOIZISCRIVNZJJ-XWJFFXCMSA-N
References
1. Dale B, Anderson C, Park KS, Kaniskan HÜ, Ma A, Shen Y, Zhang C, Xie L, Chen X, Yu X et al.. (2022)
Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2.
ACS Pharmacol Transl Sci, 5 (7): 491-507. [PMID:35837138]
2. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA et al.. (2013)
Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
Proc Natl Acad Sci USA, 110 (19): 7922-7. [PMID:23620515]
3. Zengerle M, Chan KH, Ciulli A. (2015)
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4.
ACS Chem Biol, 10 (8): 1770-7. [PMID:26035625]