Orally active purine-based inhibitors of the heat shock protein 90.

Article Details

Citation

Biamonte MA, Shi J, Hong K, Hurst DC, Zhang L, Fan J, Busch DJ, Karjian PL, Maldonado AA, Sensintaffar JL, Yang YC, Kamal A, Lough RE, Lundgren K, Burrows FJ, Timony GA, Boehm MF, Kasibhatla SR

Orally active purine-based inhibitors of the heat shock protein 90.

J Med Chem. 2006 Jan 26;49(2):817-28.

PubMed ID
16420067 [ View in PubMed
]
Abstract

Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC(50) = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H(3)PO(4) salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
9-Butyl-8-(3,4,5-Trimethoxybenzyl)-9h-Purin-6-AmineHeat shock protein HSP 90-betaEC 50 (nM)400007.237Details