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Motesanib

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Motesanib
Names
IUPAC name
N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide
Other names
AMG 706
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
  • InChI=1S/C22H23N5O/c1-22(2)14-26-19-12-16(5-6-18(19)22)27-21(28)17-4-3-9-24-20(17)25-13-15-7-10-23-11-8-15/h3-12,26H,13-14H2,1-2H3,(H,24,25)(H,27,28)
  • O=C(c2cccnc2NCc1ccncc1)Nc3ccc4c(c3)NCC4(C)C
Properties
C22H23N5O
Molar mass 373.460 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Motesanib (AMG 706) is an experimental drug candidate originally developed by Amgen[1] but is now being investigated by the Takeda Pharmaceutical Company. It is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of VEGF receptors, platelet-derived growth factor receptors, and stem cell factor receptors.[2] It is used as the phosphate salt motesanib diphosphate.

Clinical trials

Motesanib was originally investigated for effectiveness against advanced nonsquamous non-small-cell lung cancer (NSCLC), with Phase II trials indicating an effectiveness comparable to bevacizumab when they were both used in combination with paclitaxel/carboplatin.[3] However a later and more detailed Phase III trial failed to show any benefit for the treatment of NSCLC.[2][4] A second Phase III trial was started in 2012,[5] which focused on patients from Asian backgrounds (performed on the bases of subgroup analysis)[6] however this also failed to meet its primary endpoint.[7]

The drug has undergone a Phase II evaluation as first-line therapy for breast cancer[2] however this study found no evidence to support further investigation.[8] Phase II testing against persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas was also unsuccessful.[9]

There have also been 2 separate Phase II clinical trials for thyroid cancer which have both shown promising results.[10][11][12]

References

  1. ^ Stafford, edited by Rongshi Li, Jeffrey A. (2009). "Chapter 5. Discovery of Motesanib". Kinase inhibitor drugs. Hoboken, N.J.: Wiley. pp. 113–130. ISBN 978-0-470-27829-1. {{cite book}}: |first1= has generic name (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c "Amgen and Takeda's NSCLC Drug Fails in Phase III Study". 30 Mar 2011.
  3. ^ Blumenschein Jr, G. R.; Kabbinavar, F.; Menon, H.; Mok, T. S. K.; Stephenson, J.; Beck, J. T.; Lakshmaiah, K.; Reckamp, K.; Hei, Y.- J.; Kracht, K.; Sun, Y.- N.; Sikorski, R.; Schwartzberg, L. (14 February 2011). "A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer". Annals of Oncology. 22 (9): 2057–2067. doi:10.1093/annonc/mdq731.
  4. ^ Scagliotti, G. V.; Vynnychenko, I.; Park, K.; Ichinose, Y.; Kubota, K.; Blackhall, F.; Pirker, R.; Galiulin, R.; Ciuleanu, T.-E.; Sydorenko, O.; Dediu, M.; Papai-Szekely, Z.; Banaclocha, N. M.; McCoy, S.; Yao, B.; Hei, Y.-j.; Galimi, F.; Spigel, D. R. (2 July 2012). "International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer: MONET1". Journal of Clinical Oncology. 30 (23): 2829–2836. doi:10.1200/JCO.2011.41.4987. PMID 22753922.
  5. ^ "Takeda Initiates Phase 3 Trial of Motesanib in Japan and Additional Asian Countries". Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
  6. ^ Kubota, K.; Ichinose, Y.; Scagliotti, G.; Spigel, D.; Kim, J. H.; Shinkai, T.; Takeda, K.; Kim, S.- W.; Hsia, T.- C.; Li, R. K.; Tiangco, B. J.; Yau, S.; Lim, W.- T.; Yao, B.; Hei, Y.- J.; Park, K. (13 January 2014). "Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis". Annals of Oncology. 25 (2): 529–536. doi:10.1093/annonc/mdt552.
  7. ^ "Takeda Announces Phase 3 MONET-A Study Evaluating Motesanib (AMG 706) in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Does Not Meet Primary Endpoint". Takeda Pharmaceutical Company Limited. Retrieved 19 February 2015.
  8. ^ Martin, Miguel; Roche, Henri; Pinter, Tamas; Crown, John; Kennedy, M John; Provencher, Louise; Priou, Frank; Eiermann, Wolfgang; Adrover, Encarna; Lang, Istvan; Ramos, Manuel; Latreille, Jean; Jagiełło-Gruszfeld, Agnieszka; Pienkowski, Tadeusz; Alba, Emilio; Snyder, Raymond; Almel, Sachin; Rolski, Janusz; Munoz, Montserrat; Moroose, Rebecca; Hurvitz, Sara; Baños, Ana; Adewoye, Henry; Hei, Yong-Jiang; Lindsay, Mary-Ann; Rupin, Matthieu; Cabaribere, David; Lemmerick, Yasmin; Mackey, John R (April 2011). "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". The Lancet Oncology. 12 (4): 369–376. doi:10.1016/S1470-2045(11)70037-7. PMID 21429799.
  9. ^ Schilder, R.J.; Sill, M.W.; Lankes, H.A.; Gold, M.A.; Mannel, R.S.; Modesitt, S.C.; Hanjani, P.; Bonebrake, A.J.; Sood, A.K.; Godwin, A.K.; Hu, W.; Alpaugh, R.K. (April 2013). "A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: A Gynecologic Oncology Group study". Gynecologic Oncology. 129 (1): 86–91. doi:10.1016/j.ygyno.2013.01.006. PMID 23321064.
  10. ^ Motesanib Diphosphate Provides Anticancer Activity Among Patients with Progressive Thyroid Cancer, CancerConnect.com
  11. ^ Schlumberger, M. J.; Elisei, R.; Bastholt, L.; Wirth, L. J.; Martins, R. G.; Locati, L. D.; Jarzab, B.; Pacini, F.; Daumerie, C.; Droz, J.-P.; Eschenberg, M. J.; Sun, Y.-N.; Juan, T.; Stepan, D. E.; Sherman, S. I. (29 June 2009). "Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer". Journal of Clinical Oncology. 27 (23): 3794–3801. doi:10.1200/JCO.2008.18.7815. PMID 19564535.
  12. ^ Sherman, Steven I.; Wirth, Lori J.; Droz, Jean-Pierre; Hofmann, Michael; Bastholt, Lars; Martins, Renato G.; Licitra, Lisa; Eschenberg, Michael J.; Sun, Yu-Nien; Juan, Todd; Stepan, Daniel E.; Schlumberger, Martin J. (3 July 2008). "Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer". New England Journal of Medicine. 359 (1): 31–42. doi:10.1056/NEJMoa075853. PMID 18596272.
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