title: Experimental and structural testing module to analyze paralogue-specificity and affinity in the Hsp90 inhibitors series.
abstract: We here describe the first reported comprehensive analysis of Hsp90 paralogue affinity and selectivity in the clinical Hsp90 inhibitor chemotypes. This has been possible through the development of a versatile experimental assay based on a new FP-probe (16a) that we both describe here. The assay can test rapidly and accurately the binding affinity of all major Hsp90 chemotypes and has a testing range that spans low nanomolar to millimolar binding affinities. We couple this assay with a computational analysis that allows for rationalization of paralogue selectivity and defines not only the major binding modes that relay pan-paralogue binding or, conversely, paralogue selectivity, but also identifies molecular characteristics that impart such features. The methods developed here provide a blueprint for parsing out the contribution of the four Hsp90 paralogues to the perceived biological activity with the current Hsp90 chemotypes and set the ground for the development of paralogue selective inhibitors.
authors: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center , New York, New York 10021, United States.
authors: Tony
authors: T
authors: Taldone
authors: Pallav D
authors: PD
authors: Patel
authors: Maulik
authors: M
authors: Patel
authors: Hardik J
authors: HJ
authors: Patel
authors: Christopher E
authors: CE
authors: Evans
authors: Anna
authors: A
authors: Rodina
authors: Stefan
authors: S
authors: Ochiana
authors: Smit K
authors: SK
authors: Shah
authors: Mohammad
authors: M
authors: Uddin
authors: Daniel
authors: D
authors: Gewirth
authors: Gabriela
authors: G
authors: Chiosis
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D005454:Fluorescence Polarization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015335:Molecular Probes; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D018841:HSP90 Heat-Shock Proteins; D015335:Molecular Probes
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