3HEK

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

Summary for 3HEK

• Entry DOI: 10.2210/pdb3hek/pdb
• Descriptor: Heat shock protein HSP 90-alpha, [(2~{R})-2-[4-[[3,3-bis(fluoranyl)pyrrolidin-1-yl]methyl]phenyl]pyrrolidin-1-yl]-[5-chloranyl-2,4-bis(oxidanyl)phenyl]methanone, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: hsp90, alternative splicing, atp-binding, chaperone, cytoplasm, nucleotide-binding, phosphoprotein, stress response
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 2
• Total formula weight: 52134.43

Authors

Gajiwala, K.S. (deposition date: 2009-05-08, release date: 2009-09-29, Last modification date: 2024-04-03)

Primary citation

Cho-Schultz, S.,Patten, M.J.,Huang, B.,Elleraas, J.,Gajiwala, K.S.,Hickey, M.J.,Wang, J.,Mehta, P.P.,Kang, P.,Gehring, M.R.,Kung, P.P.,Sutton, S.C.
Solution-phase parallel synthesis of Hsp90 inhibitors
J.Comb.Chem., 11:860-874,

PubMed Abstract: 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.

PubMed: 19583220
DOI: 10.1021/cc900056d

Experimental method

X-RAY DIFFRACTION (1.95 Å)