| Target Validation Information | |||||
|---|---|---|---|---|---|
| TTD ID | T52624 | ||||
| Target Name | Platelet-derived growth factor receptor (PDGFR) | ||||
| Type of Target |
Successful |
||||
| Drug Potency against Target | Imatinib | Drug Info | IC50 = 37 nM | [5] | |
| Sunitinib | Drug Info | IC50 = 1 nM | [3] | ||
| Axitinib | Drug Info | IC50 = 1.6 nM | [7] | ||
| BAY-57-9352 | Drug Info | Ki = 15 nM | [8] | ||
| Motesanib | Drug Info | IC50 = 84 nM | [5] | ||
| Nilotinib | Drug Info | Ki = 71 nM | [2] | ||
| Rosiglitazone + metformin | Drug Info | Ki = 8 nM | [1] | ||
| TAK-593 | Drug Info | Ki = 4.3~13 nM | [9] | ||
| TKI258 | Drug Info | IC50 = 9 nM | [5] | ||
| Action against Disease Model | Imatinib | Drug Info | Most patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 microM (median, 0.6 microM). Patients with low IC50imatinib (IC50 < or = 0.6 microM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the lowIC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib. | [4] | |
| Sunitinib | Drug Info | IC50 in leukemia cell line Kas uMi-1: 75.7 nM | [6] | ||
| References | |||||
| REF 1 | SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 2000 Aug 1;60(15):4152-60. | ||||
| REF 2 | Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005 Feb;7(2):129-41. | ||||
| REF 3 | A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. | ||||
| REF 4 | In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood. 2005 Oct 1;106(7):2520-6. | ||||
| REF 5 | A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. | ||||
| REF 6 | Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Jul;51(1):42-8. | ||||
| REF 7 | Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 15;14(22):7272-83. | ||||
| REF 8 | An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009 Oct;6(10):569-79. | ||||
| REF 9 | Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism. Biochemistry. 2011 Feb 8;50(5):738-51. | ||||
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