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AMG706 – Multi targeted broad spectrum inhibitor

by Selleckchem | Mar 13 2012

AMG706: MULTI KINASE INHIBITOR

Tyrosine kinases are a family of enzymes which fuction as regulators of many cellular processes but the phosphorylation of proteins. This process involves the action of ATP, the kinase and the target protein complexing for the transfer via a ATP binding domain on the tyrosine kinase. Computer simulation of the conformational structure of tyrosine kinases led to the development of a highly specific molecule which inhibited the phosphorylation by preferentially binding to the receptor domain. This molecule was determined to be very successful clinically in the treatment of chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs). Imatinib is single kinase inhibitor but market driven forces have developed many tyrosine kinase inhibitors that either target single kinases or multiple kinases.

The AMG706 PDGF-R inhibitor was developed Amgen and Takeda PLc is marketed under the Motesanib [1-3]. Motesanib is administered as an oral tablet given twice per day at a dose level of 125 mg.[4] Motesanib is an inhibitor of VEGFR 1,2&3, PDGFR, c-KIT, RET and stem cell factor receptors.[5] It is used as the phosphate salt to enhance solubility.

AMG706: Physical properties and availability

AMG706 structure is loosely based on a pyrimidine core with side group substitutions, AMG706 solubility is extremely poor in aqueous solutions (maximum estimate 50 - 100µM), for all practical purposes AMG706 can be solubilized in DMSO up to 200 mg/ml and ethanolic solutions up to 40 mg/ml. Research quality material for both the free base and the diphosphate form can be obtained from various AMG706 suppliers. Research groups can buy AMG706 for AMG706 prices ranging from $62 - $200 for a 10 mg vial. Pre-clinical translational experiments have demonstrated AMG706 IC50’s in the range 2 -6 nM for VEGFR 1, 2 & 3, 84 nM for PDGFR and 8 nM for c-KIT.

AMG706: PRECLINICAL RESULTS

The AMG706 VEGFR inhibitor demonstrated a potential role against human endothelial cell proliferation and vascular permeability determined in a mouse model [6]. In a series of A431 xenografts AMG706 was observed to induce tumor reduction [1]. Analysis of the tumors indicated that AMG706 played a role in apoptosis of the endothelial cells and resulted in a reduction of vascular structure. [1;7;8] Focus of AMG706 was directed towards breast cancer [5], thyroid cancer [9], advanced solid tumors [4], Gastrointestinal stromal tumors (GISTS) [2] and in non small cell lung cancer (NSCLC) [7].

AMG706: Clinical Status:

Cases of differentiated or medullary carcinomas that are unresponsive to traditional therapy have been report as showing up to a 30% response rate with most results being a stable disease after single drug exposure. AMG706 clinical trial at phase 1 and phase 2 as a single drug in thyroid cancers has indicated that although response rate was low for tumour reduction over 80% of the patients were classified as stable disease. [10-13]. VEGF was used a biomarker for sensitivity and it was determined that a decrease to lower than baseline VEGF levels after treatment initialization indicated sensitivity to the drug. [11]. In addition to thyroid cancer, phase 1 trials with patients suffering from advanced solid tumours have been reported with results indicating acceptable tolerability, a reasonable pharmacokinetic profile and reduction of tumours [4;14-16].

Unfortunately, in 2011 Amgen and Takeda Plc indicated in a joint press release that the clinical trial known as MONET1 was being discontinued. This trial was conducted in over 1000 squamous and nonsquamous type NSCLC patients using combination therapy of motesanib, paclitaxel and carboplatin. Initial safety review data demonstrated a higher incidence of mortality in the treatment group compared to the placebo group. In addition this news, the FDA of USA indicated that AMG706 would not be getting approval for use against GIST’s stating poor improvement of prognosis as the deciding factor. AMG706 trials with breast cancer patients also are reporting negative results with the combination treatment with paclitaxel. [17] The future of this drug must now be considered uncertain although a significant amount of data remains to collected and reviewed.

References

1. Polverino A, Coxon A et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006; 66(17):8715-8721.

2. von MM. Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. Clin Colorectal Cancer 2006; 6 Suppl 1:S30-S34.

3. Azad A, Herbertson RA et al. Motesanib diphosphate (AMG 706), an oral angiogenesis inhibitor, demonstrates clinical efficacy in advanced thymoma. Acta Oncol 2009; 48(4):619-621.

4. Rosen LS, Kurzrock R et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007; 25(17):2369-2376.

5. Coxon A, Bush T et al. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. Clin Cancer Res 2009; 15(1):110-118.

6. Li C, Kuchimanchi M et al. In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans. Drug Metab Dispos 2009; 37(7):1378-1394.

7. Lee CB, Socinski MA. Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: a review of recent clinical trials. Rev Recent Clin Trials 2007; 2(2):117-120.

8. Verweij J, de JM. Multitarget tyrosine kinase inhibition: [and the winner is...]. J Clin Oncol 2007; 25(17):2340-2342.

9. Diaz-Cano SJ. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 2008; 359(25):2727.

10. Schlumberger MJ, Elisei R et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009; 27(23):3794-3801.

11. Bass MB, Sherman SI et al. Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J Clin Endocrinol Metab 2010; 95(11):5018-5027.

12. Claret L, Lu JF et al. Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer. Cancer Chemother Pharmacol 2010; 66(6):1141-1149.

13. Lu JF, Claret L et al. Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients. Cancer Chemother Pharmacol 2010; 66(6):1151-1158.

14. Rosen PJ, Sweeney CJ et al. A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors. Clin Cancer Res 2010; 16(9):2677-2687.

15. Fujisaka Y, Yamada Y et al. Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 2010; 66(5):935-943.

16. Sawaki A, Yamada Y et al. Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. Cancer Chemother Pharmacol 2010; 65(5):961-967.

17. Martin M, Roche H et al. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 2011; 12(4):369-376.