TBK1 PROTAC 3i   Click here for help

GtoPdb Ligand ID: 11661

Synonyms: compound 3i [PMID: 28692295]
Compound class: Synthetic organic
Comment: This compound (3i) is a TANK-binding kinase 1 (TBK1) PROTAC degrader [1]. The TBK1 inhibitor portion of the molecule binds the kinase and the Von Hippel-Lindau (VHL) binding portion of the molecule recruits an E3 ubiquitin ligase to the bound kinase and this leads to proteasomal degradation of the kinase protein. This PROTAC was used to evaluate TBK1 as a target in mutant KRAS cancer cells. 3i does not promote degradation of closely related IKKε which has 65% sequence homology with TBK1.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 17
Hydrogen bond donors 5
Rotatable bonds 35
Topological polar surface area 246.94
Molecular weight 1091.45
XLogP 5.61
No. Lipinski's rules broken 3
SMILES / InChI / InChIKey
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Canonical SMILES O[C@@H]1C[C@H](N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)COCCCOCCCCOCCCOc1ccc(cc1)Nc1ncc(c(n1)NCCCN(C(=O)C1CCC1)C)Br)C(=O)NCc1ccc(cc1)c1scnc1C
Isomeric SMILES Cc1c(scn1)c1ccc(cc1)CNC(=O)[C@@H]1C[C@H](CN1C(=O)[C@H](C(C)(C)C)NC(=O)COCCCOCCCCOCCCOc1ccc(cc1)Nc1ncc(c(n1)NCCCN(C)C(=O)C1CCC1)Br)O
InChI InChI=1S/C53H74BrN9O9S/c1-36-46(73-35-58-36)38-16-14-37(15-17-38)31-56-49(66)44-30-41(64)33-63(44)51(68)47(53(2,3)4)60-45(65)34-71-28-10-26-69-24-6-7-25-70-27-11-29-72-42-20-18-40(19-21-42)59-52-57-32-43(54)48(61-52)55-22-9-23-62(5)50(67)39-12-8-13-39/h14-21,32,35,39,41,44,47,64H,6-13,22-31,33-34H2,1-5H3,(H,56,66)(H,60,65)(H2,55,57,59,61)/t41-,44+,47-/m1/s1
InChI Key QMGHHBHPDDAGGO-IIWOMYBWSA-N
References
1. Crew AP, Raina K, Dong H, Qian Y, Wang J, Vigil D, Serebrenik YV, Hamman BD, Morgan A, Ferraro C et al.. (2018)
Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.
J Med Chem, 61 (2): 583-598. [PMID:28692295]