SAR-020106

Research use only, not for human use.

SAR-020106 is a potent, ATP-competitive, and selective CHK1 inhibitor with an IC50 of 13.3 nmol/L on the isolated human enzyme.SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion.

SAR-020106 is a potent, ATP-competitive, and selective CHK1 inhibitor with an IC50 of 13.3 nmol/L on the isolated human enzyme.SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.SAR-020106 potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

SAR-020106 (0.1-1 μM; 23 hours) abrogates an Etoposide-induced S and G2 arrest.SAR-020106 is capable of abrogating Etoposide-induced cell cycle arrest with an IC50 of 55 nM and 91 nM in HT29 and SW620 cells, respectively. SAR-020106 is relatively nontoxic with a GI50 of 0.48 μM in HT29 and 2 μM in SW620, resulting in an activity index of 8.7 and 22, respectively. SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion.

SAR-020106 (40 mg/kg; i.p.; administered on days 0, 1, 7, 8, 14, and 15) in combination with Irinotecan potentiates the antitumor activity in SW620 xenografts. Animal Model:Nude mice bearing SW620 xenograft tumors Dosage:40 mg/kg Administration:I.p.; administered on days 0, 1, 7, 8, 14, and 15 Result:There was a clear decrease in tumor growth associated with the combination with tumors reaching 300% by 12.5 days.

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Angiogenesis

Chk

CHK1

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1184843-57-9

382.85

C19H19ClN6O

>98% (HPLC)

In Vitro:?DMSO : 5 mg/mL (13.06 mM)

C[C@H](CN(C)C)Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N

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(-20℃)

With Ice Pack

≥ 2 years