MOTESANIB IN MULTIPLE ROLES

by Selleckchem | Mar 19 2012

Introduction: Multi-pathway inhibition

One aspect of kinase inhibition that has become apparent during the testing of various small molecule inhibitors is that single agent therapy is only applicable in a small segment of the patients being treated [1]. Different molecules inhibiting similar areas of the same pathway can have a different effect on which section of the patient population will respond. Combinations of single agents which have one main target kinase have demonstrated a greater efficacy when compared to the profile of the single agent alone. Hence the conclusion drawn from this is that multiple kinase inhibition is the more effective treatment path to follow [2]. The subsequent development of multi-kinase inhibitors was triggered by the difficulty in combining single target molecules in a treatment profile. Treatment schedules were different, doses were different, toxicity was increased due to two or more drug treats rather than just the one and patient variability meant that a generalized schedule of treatment was a difficult compromise [3-5]. Therefore, small molecules which targeted different pathways with a similar IC50 such as Sorafenib [6] and Pazopanib [7] are being intensely sort after.

One such molecule that has reached clinical testing stages is Motesanib PDGF-R inhibitor which has activity in roughly equal proportions towards PDGF-R, VEGF-r and cKIT. The two pathways VEGF and PDGF are closely related in terms of final objective. However, there is no crossover point in these pathways making then independent of each other. VEGF is an acronym for “vascular epithelial growth factor” and is heavily involved in the formation of vascular structure in the expanding tumor. PDGF stands for the “platelet derived growth factor” which regulates such processes as cell division and cell survival [3;8]. The last pathway affected is cKIT also known as SCFR which stands for the “stem cell growth factor” and this regulates the growth, proliferation and differentiation of cells.

Motesanib: Properties and availability

Since motesanib is targeted against three different pathways the importance of the relative sensitivity for its action becomes very important. The Motesanib IC50 quoted are the averages from several investigations and against several different isoforms- VEGFR is the most sensitive with an IC⁵⁰of 4 ± 2 nM, next is c-KIT with an IC⁵⁰ of 8nM and the least sensitivity is the PDGFR with an IC⁵⁰ of 84nM . Structurally Motesanib contains elements from single target inhibitors of each pathway, The Motesanib structure contains a carboxamide group, an indol group and pryidine groups arranged in a similar fashioned to urea derivatives. Motesanib solubility in an aqueous solution is extremely low with buffer concentrations in the range 50-100 µM achievable; however, Motesanib is soluble in both DMSO (200mg/ml) and Ethanol (40 mg/ml). Motesanib suppliers provide the solid powder as the Motesanib diphosphate form which is stable at -20°C [9]. The Motesanib stability in solution is not given but and expiration date of 2 years is recommended. To buy Motesanib is possible from several Motesanib suppliers with Motesanib prices ranging from $62 up to $595 for 50 mg of material.

Motesanib: Preclinical and Clinical status

Marketed by the Amgen and Takeda pharmaceutical company the Motesanib VEGFR inhibitor was previously known as AMG706 under which code it was screened for activity [10-12]. Results suggested that Motesanib was active in NSCLC [13], breast [14] and thyroid cancers and in vitro cell culture demonstrated the accuracy of this statement. Quickly moved to clinical trials Motesanib went through phase I and II trials in NSCLC, GIST and breast cancer. Results recently obtained indicate that Motesanib at phase III in NCSLS did not improve the quality of life for these patients and survival time was equal to the normal first line therapy. Therefore, the announcement was made that Motesanib would not be continuing at phase III for NSCLC patients [10]. Motesanib clinical trials are still proceeding in breast cancer and thyroid cancer. The results are expected within 2012.

References

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13. Raghav KP, Blumenschein GR. Motesanib and advanced NSCLC: experiences and expectations. Expert Opin Investig Drugs 2011; 20(6):859-869.

14. 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.