MS15   Click here for help

GtoPdb Ligand ID: 12216

Synonyms: compound 62 [PMID: 36197750]
Compound class: Synthetic organic
Comment: MS15 is a PROTAC that targets the AKT serine/threonine kinases for proteasomal degradation [1]. Its AKT binding domain is the allosteric pan-AKT inhibitor miransertib (ARQ-092). This is joined to a von Hippel-Lindau (VHL)-recruiting ligand by a short linker. MS15 selectively and significantly degrades AKT1 and AKT2 and suppresses proliferation in cancer cells with KRAS/BRAF mutations. AKT3 is expressed at very low levels in the SW620 cells used in the assay, so the degrading effect of MS15 on AKT3 is unclear. An earlier AKT-directed PROTAC (MS21) with an ATP-competitive AKT inhibitor (capivasertib/AZD5363) as warhead was not anti-proliferative against KRAS/BRAF mutation-carrying cells.
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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 6
Rotatable bonds 29
Topological polar surface area 264.09
Molecular weight 1114.45
XLogP 10.29
No. Lipinski's rules broken 5
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 O=C(CCc1cccc(c1)c1ccc2c(n1)n(c1ccc(cc1)C1(N)CCC1)c(n2)c1cccnc1N)NCCCCCCCCCCC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)N[C@H](c1ccc(cc1)c1scnc1C)C)O
Isomeric SMILES O=C(NCCCCCCCCCCC(=O)N[C@@H](C(C)(C)C)C(=O)N1[C@H](C(=O)N[C@@H](C)c2ccc(c3c(C)ncs3)cc2)C[C@@H](O)C1)CCc1cc(c2nc3c(nc(c4c(N)nccc4)n3c3ccc(C4(N)CCC4)cc3)cc2)ccc1
InChI InChI=1S/C64H79N11O5S/c1-41(44-22-24-45(25-23-44)56-42(2)69-40-81-56)70-61(79)53-38-49(76)39-74(53)62(80)57(63(3,4)5)73-55(78)20-12-10-8-6-7-9-11-13-35-67-54(77)32-21-43-17-14-18-46(37-43)51-30-31-52-60(71-51)75(59(72-52)50-19-15-36-68-58(50)65)48-28-26-47(27-29-48)64(66)33-16-34-64/h14-15,17-19,22-31,36-37,40-41,49,53,57,76H,6-13,16,20-21,32-35,38-39,66H2,1-5H3,(H2,65,68)(H,67,77)(H,70,79)(H,73,78)/t41-,49+,53-,57+/m0/s1
InChI Key XYGBNRINQSQNJG-IQDHSYJRSA-N
References
1. Yu X, Xu J, Cahuzac KM, Xie L, Shen Y, Chen X, Liu J, Parsons RE, Jin J. (2022)
Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells.
J Med Chem, 65 (20): 14237-14260. [PMID:36197750]