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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2D Structure
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Physico-chemical Properties
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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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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
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