compound 16 [PMID: 31653597]   Click here for help

GtoPdb Ligand ID: 10713

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 16 is a hybrid, hetero-bifunctional molecule that comprises a PCSK9-binding ligand connected to an Arg(Boc)3 moiety [3]. This latter motif acts as a ubiquitin-independent proteasome-recruiting element [1-2,4] that in this case was used to facilitate ligand-induced degradation of PCSK9 protein. X-ray co-crystallisation shows that compound 16 binds to an allosteric site on PCSK9 and has no intrinsic effect on PCSK9 function. The X-ray structure also reveals that the Arg(Boc)3 moiety extents outwith the binding pocket which enables interactions with components of the degradation complex. Targeted degradation of PCSK9 is being examined as an alternative to anti-PCSK9 monoclonals (already in the clinic) or small-molecule inhibitors of the PCSK9/low-density lipoprotein (LDL) receptor protein-protein interaction (which is very difficult to drug due to the 3D structure of the interaction domains) as a novel mechanism to decrease LDL cholesterol levels.

The Arg(Boc)3 motif is used as an alternative to the more widely utilised ubiquitin-proteasome system recruiting elements that engage the VHL and CRBN ubiquitin ligases, and which have been used in a number of previously reported PROTACs.
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Ligand Activity Visualisation 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 19
Hydrogen bond donors 7
Rotatable bonds 33
Topological polar surface area 303.7
Molecular weight 1076.47
XLogP 7.32
No. Lipinski's rules broken 4
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 CC(OC(=O)N[C@H](C(=O)NCCOCCOc1cc2CCN[C@](c2cc1Oc1ccc(c(c1)F)c1ccc(cc1)C(=O)O)(C)CC(=O)Nc1nccs1)CCCN/C(=N/C(=O)OC(C)(C)C)/NC(=O)OC(C)(C)C)(C)C
Isomeric SMILES CC(OC(=O)N[C@H](C(=O)NCCOCCOc1cc2CCN[C@](c2cc1Oc1ccc(c(c1)F)c1ccc(cc1)C(=O)O)(C)CC(=O)Nc1nccs1)CCCN/C(=N/C(=O)OC(C)(C)C)/NC(=O)OC(C)(C)C)(C)C
InChI InChI=1S/C53H69FN8O13S/c1-50(2,3)73-47(67)59-39(12-11-20-56-45(61-48(68)74-51(4,5)6)62-49(69)75-52(7,8)9)43(64)55-22-24-70-25-26-71-40-28-34-19-21-58-53(10,31-42(63)60-46-57-23-27-76-46)37(34)30-41(40)72-35-17-18-36(38(54)29-35)32-13-15-33(16-14-32)44(65)66/h13-18,23,27-30,39,58H,11-12,19-22,24-26,31H2,1-10H3,(H,55,64)(H,59,67)(H,65,66)(H,57,60,63)(H2,56,61,62,68,69)/t39-,53+/m0/s1
InChI Key BOAJXEFAPWTSFX-FXASYPJLSA-N
Classification Click here for help
Compound class Synthetic organic
Ligand families/groups PROTACs, molecular glues and other degraders
IUPAC Name Click here for help
4-[4-[[(1R)-6-[2-[2-[[(2S)-5-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]ethoxy]ethoxy]-1-methyl-1-[2-oxo-2-(1,3-thiazol-2-ylamino)ethyl]-3,4-dihydro-2H-isoquinolin-7-yl]oxy]-2-fluorophenyl]benzoic acid
Database Links Click here for help
GtoPdb PubChem SID 404859160
PubChem CID 139592542
RCSB PDB Ligand 063
Search Google for chemical match using the InChIKey BOAJXEFAPWTSFX-FXASYPJLSA-N
Search Google for chemicals with the same backbone BOAJXEFAPWTSFX
UniChem Compound Search for chemical match using the InChIKey BOAJXEFAPWTSFX-FXASYPJLSA-N
UniChem Connectivity Search for chemical match using the InChIKey BOAJXEFAPWTSFX-FXASYPJLSA-N