ARRY-380 analog, an analog of ARRY-380 (Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib) which is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent.
理化性质和储存条件
| Molecular Weight (MW) | 569.63 |
|---|
| Formula | C29H27N7O4S |
|---|
| CAS No. | 937265-83-3 (ARRY-380 analog); |
|---|
| Storage | -20℃ for 3 years in powder form |
|---|
| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 100 mg/mL (175.55 mM) |
|---|
| Water: <1 mg/mL |
| Ethanol: 3 mg/mL (5.26 mM) |
| Solubility (In vivo) | CC1=CC(NC2=C3C=C(C4=CC=C(CNCCS(=O)(C)=O)O4)C=CC3=NC=N2)=CC=C1OC5=CC6=NC=NN6 C=C5 |
|---|
| Synonyms | Irbinitinib analog; Tucatinib analog; ARRY-380 analog; ONT380 analog; ONT 380 analog; ONT-380 analog |
|---|
实验参考方法
| In Vitro | In vitro activity: ARRY-380 analog, an analog of ARRY-380 (Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib) which is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent.
Kinase Assay: Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib, is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent.
Cell Assay: ONT-380 has nanomolar activity against purified HER2 enzyme and is approximately 500-fold selective for HER2 versus EGFR in cell-based assays. In the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. |
|---|
| In Vivo | In the ARRY-380-treated-group, 75% of the animals are alive on Day 43. ARRY-380 and its active metabolite causes a significant reduction in brain pErbB2 (80%). ARRY-380 demonstrates significant dose-related tumor growth inhibition (TGI; 50% at 50 mg/kg/d and 96% at 100 mg/kg/d) with numerous partial regressions (>50% reduction from baseline size) at the higher dose level in 9/12 animals. ARRY-380 (50 mg/kg/d) in combination with trastuzumab shows a 98% TGI with complete regressions in 9/12 animals and two partial regressions. At dose of 100 mg/kg/d of ARRY-380 in combination with trastuzumab, there is 100% TGI and all animals have complete responses. |
|---|
| Animal model | Mice with SKOV-3 tumor |
|---|
| Formulation & Dosage | 200 mg/kg/d; oral |
|---|
| References | Clin Cancer Res. 2017 Jul 15;23(14):3529-3536. |
|---|
m.cnreagent.com