3hek

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3hek, resolution 1.95Å ()
Ligands: ,
Gene: HSP90, HSP90A, HSP90AA1, HSPC1, HSPCA (Homo sapiens)
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Contents

HSP90 N-terminal domain in complex with 1-{4-[(2R)-1-(5-chloro-2,4-dihydroxybenzoyl)pyrrolidin-2-yl]benzyl}-3,3-difluoropyrrolidinium

Publication Abstract from PubMed

As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.

Solution-phase parallel synthesis of Hsp90 inhibitors., Cho-Schultz S, Patten MJ, Huang B, Elleraas J, Gajiwala KS, Hickey MJ, Wang J, Mehta PP, Kang P, Gehring MR, Kung PP, Sutton SC, J Comb Chem. 2009 Sep-Oct;11(5):860-74. PMID:19583220

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

3hek is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Cho-Schultz S, Patten MJ, Huang B, Elleraas J, Gajiwala KS, Hickey MJ, Wang J, Mehta PP, Kang P, Gehring MR, Kung PP, Sutton SC. Solution-phase parallel synthesis of Hsp90 inhibitors. J Comb Chem. 2009 Sep-Oct;11(5):860-74. PMID:19583220 doi:10.1021/cc900056d

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