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|
|Related ATM/ATR Products|
Gartisertib (VX-803) is an ATP-competitive, orally active, selective ATR inhibitor with Ki<150 pM. Gartisertib inhibits atR-driven phosphorylation of checkpoint kinase-1 (Chk1) with an IC50 value of 8 nM. It has antitumor activity.
RP-3500 (ATR inhibitor 4) is an orally potent, selective ATR kinase inhibitor (ATRi) in biochemical assays IC50 1.00 nM. The RP-3500 is 30 times more selective to ATR (IC).50=120 nM), which is 2,000 times > ATM, DNA-PK, and PI3Kα kinase.
AZ32 is an orally bioavailable and blood-brain barrier-(BBB)penetrating inhibitor of ATM with IC50 of <6.2 nM and 0.31 μM for ATM enzyme in cell.
AZD0156 is a potent, selective and orally active ATM inhibitor with an IC50 of 0.58 nM. AZD0156 inhibits ATM mediated signal transduction, prevents DNA damage checkpoint activation, damages DNA damage repair, and induces tumor cell apoptosis.
AZD1390 is currently the most effective and highly selective ATM inhibitor with an IC50 of 0.78 nM, oral activity and the ability to cross the blood-brain barrier. In vivo, AZD1390 combined with radiotherapy effectively inhibited tumor growth.
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