AZD7762

APIM050102: AZD7762 Hydrochloride

CAS No.: 1246094-78-9 (HCl), 860352-01-8 (free base)

IUPAC/Chemical Name: (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide hydrochloride

Molecular Formula: C₁₇H₁₉FN₄O₂S •HCl •H₂O

Molecular Weight: 416.9

Purity: >99.5% chemical and optical purity (HPLC and chiral HPLC at 214 and 254 nm).
QC: HPLC-MS, ¹HNMR, Chiral HPLC and Quantitative Elemental Analysis.

Solubility: In DMSO, water.

Storage: Store at 0°C (short term), -20°C (long term), desiccated.

Background Information:

AZD7762 is a potent ATP-competitive checkpoint kinase inhibitor with IC50s at 5 nM and <10 nM for CHK1 and CHK2, respectively, currently in clinical trials.

In Vitro: AZD7762 (AZD-7762) is an equally potent inhibitor of Chk1 and Chk2. AZD7762 potently inhibits Chk1 and Chk2, abrogates DNA damage-induced S and G₂ checkpoints, enhances the efficacy of NSC 613327 and SKF 104864A, and modulates downstream checkpoint pathway proteins. AZD7762 also inhibits Chk1 phosphorylation of a cdc25C peptide (IC₅₀ = 5nM). Kinetic characterization suggests that AZD7762 binds in the ATP-binding site of Chk1 and is thought to compete directly for ATP binding in a reversible manner (K_i = 3.6nM.). AZD7762 is shown to abrogate the G₂ arrest induced by Camptothecin (EC₅₀ = 10nM) (n=12) and maximal abrogation in the range of 100 nM [1].

In Vivo: In the rat H460-DNp53 xenograft study, AZD7762 (AZD-7762) potentiates the antitumor activity of NSC 613327 in a dose-dependent manner by a decrease in %T/C with increasing dose (48% and 32%, 10 and 20 mg/kg AZD7762, respectively). In the mouse xenograft study in combination with CPT11, SW620 established tumors are treated with vehicle, CPT11 alone, AZD7762 alone, or AZD7762 in combination with CPT-11. AZD7762 alone shows insignificant antitumor activity, whereas CPT11 alone displays striking and significant activity (%T/C with increasing dose is 9 and 1, respectively ). In combination with AZD7762, %T/C increases significantly to -66% and -67%, respectively [1] . AZD7762 combination with CX5461 induces cancer cell death of Tp53-null (Tp53^-/-) Eμ-Myc lymphoma cells [2].

Reference:

1. Zabludoff, S. D.; Deng, C.; Grondine, M. R.; Sheehy, A. M.; Ashwell, S.; Caleb, B. L.; Green, S.; Haye, H. R.; Horn, C. L.; Janetka, J. W.; Liu, D.; Mouchet, E.; Ready, S.; Rosenthal, J. L.; Queva, C.; Schwartz, G. K.; Taylor, K. J.; Tse, A. N.; Walker, G. E.; White, A. M.; “AZD7762, A Novel Checkpoint Kinase Inhibitor, Drives Checkpoint Abrogation and Potentiates DNA-Targeted Therapies”, Mol. Cancer Ther. 2008, 7, 2955-2966.

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