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Journal of Medicinal Chemistry
12. Hon, W.C.; Wilson, M.I.; Harlos, K.; Claridge, T.D.;
are thankful to Dr. Lars Sansberg for help with computatioꢀ
Schofield, C.J.; Pugh, C.W.; Maxwell, P.H.; Ratcliffe, P.J.; Stuꢀ
art, D.I.; Jones, E.Y. Structural Basis for the Recognition of
Hydroxyproline in HIFꢀ1 alpha by VHL. Nature 2002, 417, 975ꢀ
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13. Louie, R.J.; Padró, M.; Giaccia, A.J.; Chan, D.A. Small Molꢀ
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into Mounting Orchestrated Survival and Repair Responses. J.
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15. Muchnik, E.; Kaplan, J. HIF Prolyl Hydroxylase Inhibitors for
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16. Buckley, D.L., Van Molle, I., Gareiss, P.C., Tae, H.S.,
Michel, J., Noblin, D.J., Jorgensen, W.L., Ciulli, A., Crews, C.M.
Targeting the von HippelꢀLindau E3 Ubiquitin Ligase Using
Small Molecules to Disrupt the VHL/HIFꢀ1α Interaction. J. Am.
Chem. Soc. 2012, 134, 4465–4468.
17. Van Molle, I.; Thomann, A.; Buckley, D. L.; So, E. C.; Lang,
S.; Crews, C. M.; Ciulli, A. Dissecting FragmentꢀBased Lead
Discovery at the Von HippelꢀLindau Protein:Hypoxia Inducible
Factor 1α ProteinꢀProtein Interface. Chem. Biol. 2012, 19,
1300–1312.
18. Buckley, D.L., Gustafson, J.L., Van Molle, I., Roth, A.G.,
Tae, H.S., Gareiss, P.C., Jorgensen, W.L., Ciulli, A., Crews,
C.M. Small Molecules Inhibitors of the Interaction Between the
E3 Ligase VHL and HIF1α. Angew. Chem. Int. Ed. 2012, 51,
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19. Dias, D. M.; Van Molle, I.; Baud, M. G. J.; Galdeano, C.;
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tion Using Chemical Probes. Nat. Chem. Biol. 2013, 9, 195–
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21. Bochevarov, A.D.; Harder, E.; Hughes, T.F.; Greenwood,
J.R.; Braden, D.A.; Philipp, D.M.; Rinaldo, D.; Halls, M.D.;
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22. Buckley, D. L.; Crews, C. M. SmallꢀMolecule Control of
Intracellular Protein Levels Through Modulation of the Ubiquitin
Proteasome System. Angew. Chem. Int. Ed. 2014, 53, 2312–
2330.
23. VCCLAB, Virtual Computational Chemistry Laboratory,
V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl,
P.; Palyulin, V.A.; Radchenko, E.V.; Zefirov, N.S.; Makarenko,
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nal calculations and to Martina Casale for help with VBC
protein expression. We are also thankful to Diamond Light
Source for beamtime (proposal mx8268) and beamline supꢀ
port at I03 and I04 and the European Synchrotron Radiation
Facility for beamtime (proposal mx1481) and beamline supꢀ
port at ID14ꢀ4 and BM14.
ABBREVIATIONS
CODD, Cꢀterminal oxygenꢀdegradation domain; GE, group
efficiency; GLE, group lipophilicity efficiency; HIFꢀ1α, hyꢀ
poxia inducible factor 1 alpha; ITC, isothermal titration caloꢀ
rimetry; LE, ligand efficiency; LHS, leftꢀhand side; NODD,
Nꢀterminal oxygenꢀdegradation domain; O/N, overnight,
PHD, prolyl hydroxylases; PPI, proteinꢀprotein interaction;
RHS, rightꢀhand site; SAR, structureꢀactivity relationships;
UPS, ubiquitinꢀproteasome system; VBC, VHLꢀEloBꢀEloC;
pVHL, von HippelꢀLindau protein.
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