2012
DOI: 10.1124/dmd.111.043000
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In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

Abstract: ABSTRACT:Inhibition of heat shock protein 90 (HSP90) results in the degradation of oncoproteins that drive malignant progression and induce cell death, thus making HSP90 a potential target of cancer therapy. 6-Chloro-9-(4-methoxy-3, 5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models. It is currently in phase II clinical trials for the oral treatment of breast cancer. The objective of this study was to obtain bot… Show more

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Cited by 12 publications
(21 citation statements)
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“…The formation of metabolite M10 was primarily catalyzed by AO (Xu et al, 2012). To determine and compare the kinetic activity of M10 formation in different species, BIIB021 was incubated in the liver cytosolic fractions of rat, dog, monkey, mouse, and human.…”
Section: Kinetic Analysis Of M10 Formationmentioning
confidence: 99%
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“…The formation of metabolite M10 was primarily catalyzed by AO (Xu et al, 2012). To determine and compare the kinetic activity of M10 formation in different species, BIIB021 was incubated in the liver cytosolic fractions of rat, dog, monkey, mouse, and human.…”
Section: Kinetic Analysis Of M10 Formationmentioning
confidence: 99%
“…Therefore, M10 was identified as a hydroxylated metabolite, an isomer of M7. It was also identified as a metabolite in liver cytosolic fraction (Xu et al, 2012) and had the same retention time in LC as the synthetic standard (M10). To further confirm the exact location of hydroxylation, M10 was isolated from monkey liver cytosolic incubation, and its 1 H NMR spectra was compared with that of BIIB021 (Fig.…”
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confidence: 92%
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