Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90.

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He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu N, Immormino RM, Gewirth DT, Chiosis G

Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90.

J Med Chem. 2006 Jan 12;49(1):381-90.

PubMed ID
16392823 [ View in PubMed
]
Abstract

Hsp90 is a chaperone protein that allows cancer cells to tolerate the many components of dysregulated pathways. Its inactivation may result in targeting multiple molecular alterations and, thus, in reverting the transformed phenotype. The PU-class, a purine-scaffold Hsp90 inhibitor series, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of this class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. The study identifies water soluble derivatives (>5 mM in PBS pH 7.4) of nanomolar potency (IC(50) approximately 50 nM) in cellular and animal models of cancer. Binding affinities of these compounds for Hsp90 correlate well with their biological activities. When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
8-(6-BROMO-BENZO[1,3]DIOXOL-5-YLSULFANYL)-9-(3-ISOPROPYLAMINO-PROPYL)-ADENINEHeat shock protein HSP 90-betaEC 50 (nM)13300N/AN/ADetails
8-(6-BROMO-BENZO[1,3]DIOXOL-5-YLSULFANYL)-9-(3-ISOPROPYLAMINO-PROPYL)-ADENINEHeat shock protein HSP 90-betaEC 50 (nM)38.8N/AN/ADetails
8-(6-BROMO-BENZO[1,3]DIOXOL-5-YLSULFANYL)-9-(3-ISOPROPYLAMINO-PROPYL)-ADENINEHeat shock protein HSP 90-betaEC 50 (nM)55.4N/AN/ADetails
8-(6-BROMO-BENZO[1,3]DIOXOL-5-YLSULFANYL)-9-(3-ISOPROPYLAMINO-PROPYL)-ADENINEHeat shock protein HSP 90-betaIC 50 (nM)205N/AN/ADetails
8-(6-BROMO-BENZO[1,3]DIOXOL-5-YLSULFANYL)-9-(3-ISOPROPYLAMINO-PROPYL)-ADENINEHeat shock protein HSP 90-betaEC 50 (nM)5200N/AN/ADetails