AZ31 is a potent and highly selective ATM inhibitor with an IC50 of <0.0012 μM. AZ31 is the first selective orally active and bioavailable ATM kinase inhibitor.
In vivo, pharmacokinetic investigation of AZ31 as a single agent and in combination with irinotecan revealed that plasma concentrations of AZ31 were highest 1-hour after administration followed by a stepwise decrease at 3, 6 and 16 hour in the combination sensitive CRC098.
|Cell lines||CRC (metastatic colorectal cancer) cell lines: HCT15, HCT116, RKO, CaCo2, LS123 and LOVO|
|Preparation method||Six CRC cell lines were treated with AZ31 (dose 1.25, 2.5 or 5 μmol/L), SN38 (0.3125 -20 nM) or AZ31 + SN38 and proliferation was determined by an SRB assay.|
|Concentrations||1.25, 2.5 or 5 μmol/L|
|Incubation time||72 hours|
|Animal models||CRC PDX models (Four-to-six week-old female athymic nude mice with implanted patient-derived colorectal adenocarcinoma tumor)|
|Formulation||10% v/v DMSO + 90% v/v Captisol at 30% w/v|
|Dosages||100 mg/kg-daily × 3|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 40 mg/mL|
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