Motesanib
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MedKoo CAT#: 201934

CAS#: 453562-69-1 (free base)

Description: Motesanib, also known as AMG-706, is the orally bioavailable multiple-receptor tyrosine kinase inhibitor with potential antineoplastic activity. Motesanib selectively targets and inhibits vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR), kit, and Ret receptors, thereby inhibiting angiogenesis and cellular proliferation.


Chemical Structure

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Motesanib
CAS# 453562-69-1 (free base)

Theoretical Analysis

MedKoo Cat#: 201934
Name: Motesanib
CAS#: 453562-69-1 (free base)
Chemical Formula: C22H23N5O
Exact Mass: 373.1902
Molecular Weight: 373.46
Elemental Analysis: C, 70.76; H, 6.21; N, 18.75; O, 4.28

Price and Availability

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10.0mg USD 150.0 Same Day
25.0mg USD 250.0 Same Day
50.0mg USD 450.0 Same Day
100.0mg USD 650.0 Same Day
200.0mg USD 950.0 Same Day
500.0mg USD 1650.0 Same Day
1.0g USD 2850.0 2 Weeks
2.0g USD 3850.0 2 Weeks
5.0g USD 5850.0 2 Weeks
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Related CAS #: 453562-69-1 (free base)   857876-30-3 (phosphate)  

Synonym: AMG 706; AMG706; AMG706; motesanib free base

IUPAC/Chemical Name: N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4- ylmethyl)amino]pyridine-3-carboxamide

InChi Key: RAHBGWKEPAQNFF-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=C(C1=CC=CN=C1NCC2=CC=NC=C2)NC3=CC4=C(C=C3)C(C)(C)CN4

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Motesanib is a ATP-competitive inhibitor of VEGFR1/2/3 with IC50s of 2 nM/3 nM/6 nM, respectively.
In vitro activity: One of the major findings of this study was that motesanib significantly increased the sensitivity of ABCB1 overexpressing KB-C2 drug selected cell line to paclitaxel, colchicine and vincristine, which are substrates of ABCB1 transporter. The motesanib-induced enhancement in the sensitivity of KB-C2 cells to the substrates was represented by a significant decrease in the IC50 values for the aforementioned substrates in the presence of motesanib in the MTT assay, a measurement of cell survival (Table 1). The motesanib-induced potentiation was selective because at the concentrations used in this study (1 µM and 3 µM), motesanib (1) did not produce a significant toxic effect on the parental KB-3-1 cell (non-overexpressing) and (2) failed to potentiate the effect of the substrate drugs on the parental KB-3-1 cells. Reference: Biochem Pharmacol. 2014 Aug 15; 90(4): 367–378. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133117/
In vivo activity: Mice were injected intravenously with Evans blue dye and Motesanib (50 mg/kg) and subjected to the Miles assay. Motesanib reduced the extravasation of Evans blue in the tumor, but not the skin, indicating that Motesanib inhibited tumor vascular permeability (Fig. 6A). This finding is consistent with previous studies that demonstrated an inhibition of VEGF-induced vascular permeability by Motesanib administration. By immunohistochemistry, this study confirmed that Motesanib suppressed the VEGFR2 tyrosine kinase activity, but not the expression of VEGFR2 (Supplementary Fig. S3). This study next examined the response of endothelial PKA activity to Motesanib by in vivo FRET imaging. Motesanib robustly activated PKA in the endothelial cells of the tumors, but not in the endothelial cells of the subcutaneous tissues (Fig. 6B), indicating that VEGFR played a major role in the suppression of PKA. Notably, Motesanib had no effect on the ERK activities in tumor and normal endothelial cells (Fig. 6C). The lack of effect on ERK activity is probably due to the low basal ERK activity. In fact, when ERK activity in tumor endothelial cells was elevated by VEGF, Motesanib markedly decreased ERK activity (Supplementary Fig. S4A–S4C). Reference: Cancer Res. 2016 Sep 15;76(18):5266-76. https://cancerres.aacrjournals.org/content/76/18/5266.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 87.5 234.3
Ethanol 8.0 21.42

Preparing Stock Solutions

The following data is based on the product molecular weight 373.46 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Wang YJ, Kathawala RJ, Zhang YK, Patel A, Kumar P, Shukla S, Fung KL, Ambudkar SV, Talele TT, Chen ZS. Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1. Biochem Pharmacol. 2014 Aug 15;90(4):367-78. doi: 10.1016/j.bcp.2014.06.006. Epub 2014 Jun 14. PMID: 24937702; PMCID: PMC4133117. 2. Caenepeel S, Renshaw-Gegg L, Baher A, Bush TL, Baron W, Juan T, Manoukian R, Tasker AS, Polverino A, Hughes PE. Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors. J Exp Clin Cancer Res. 2010 Jul 15;29(1):96. doi: 10.1186/1756-9966-29-96. PMID: 20633291; PMCID: PMC2912835. 3. Yamauchi F, Kamioka Y, Yano T, Matsuda M. In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability. Cancer Res. 2016 Sep 15;76(18):5266-76. doi: 10.1158/0008-5472.CAN-15-3534. Epub 2016 Aug 3. PMID: 27488524. 4. Rho CR, Kang S, Park KC, Yang KJ, Choi H, Cho WK. Antiangiogenic effects of topically administered multiple kinase inhibitor, motesanib (AMG 706), on experimental choroidal neovascularization in mice. J Ocul Pharmacol Ther. 2015 Feb;31(1):25-31. doi: 10.1089/jop.2014.0023. PMID: 25255037; PMCID: PMC4286588.
In vitro protocol: 1. Wang YJ, Kathawala RJ, Zhang YK, Patel A, Kumar P, Shukla S, Fung KL, Ambudkar SV, Talele TT, Chen ZS. Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1. Biochem Pharmacol. 2014 Aug 15;90(4):367-78. doi: 10.1016/j.bcp.2014.06.006. Epub 2014 Jun 14. PMID: 24937702; PMCID: PMC4133117. 2. Caenepeel S, Renshaw-Gegg L, Baher A, Bush TL, Baron W, Juan T, Manoukian R, Tasker AS, Polverino A, Hughes PE. Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors. J Exp Clin Cancer Res. 2010 Jul 15;29(1):96. doi: 10.1186/1756-9966-29-96. PMID: 20633291; PMCID: PMC2912835.
In vivo protocol: 1. Yamauchi F, Kamioka Y, Yano T, Matsuda M. In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability. Cancer Res. 2016 Sep 15;76(18):5266-76. doi: 10.1158/0008-5472.CAN-15-3534. Epub 2016 Aug 3. PMID: 27488524. 2. Rho CR, Kang S, Park KC, Yang KJ, Choi H, Cho WK. Antiangiogenic effects of topically administered multiple kinase inhibitor, motesanib (AMG 706), on experimental choroidal neovascularization in mice. J Ocul Pharmacol Ther. 2015 Feb;31(1):25-31. doi: 10.1089/jop.2014.0023. PMID: 25255037; PMCID: PMC4286588.

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1: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. doi: 10.1200/JCO.2017.72.7297. Epub 2017 Sep 13. PubMed PMID: 28902534.

2: Torok S, Rezeli M, Kelemen O, Vegvari A, Watanabe K, Sugihara Y, Tisza A, Marton T, Kovacs I, Tovari J, Laszlo V, Helbich TH, Hegedus B, Klikovits T, Hoda MA, Klepetko W, Paku S, Marko-Varga G, Dome B. Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors. Theranostics. 2017 Jan 1;7(2):400-412. doi: 10.7150/thno.16767. eCollection 2017. PubMed PMID: 28042343; PubMed Central PMCID: PMC5197073.

3: Skouras VS, Maragkos C, Grapsa D, Syrigos KN. Targeting Neovasculature with Multitargeted Antiangiogenesis Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer. BioDrugs. 2016 Oct;30(5):421-439. Review. PubMed PMID: 27670779.

4: Song J, Kim SB, Kim KH, Kim TN, Lee KH. A case report of motesanib-induced biliary sludge formation causing obstructive cholangitis with acute pancreatitis treated by endoscopic sphincterotomy. Medicine (Baltimore). 2016 Sep;95(37):e4645. doi: 10.1097/MD.0000000000004645. PubMed PMID: 27631212; PubMed Central PMCID: PMC5402555.

5: Yamauchi F, Kamioka Y, Yano T, Matsuda M. In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability. Cancer Res. 2016 Sep 15;76(18):5266-76. doi: 10.1158/0008-5472.CAN-15-3534. Epub 2016 Aug 3. PubMed PMID: 27488524.

6: Gosselin NH, Mouksassi MS, Lu JF, Hsu CP. Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients. Clin Pharmacol Drug Dev. 2015 Nov;4(6):463-72. doi: 10.1002/cpdd.196. Epub 2015 Jul 23. PubMed PMID: 27137719.

7: Kaya TT, Altun A, Turgut NH, Ataseven H, Koyluoglu G. Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells. Asian Pac J Cancer Prev. 2016;17(3):1103-10. PubMed PMID: 27039732.

8: Tarshis S, Maltzahn J, Loomis Z, Irwin DC. Preventing High Altitude Cerebral Edema in Rats with Repurposed Anti-Angiogenesis Pharmacotherapy. Aerosp Med Hum Perform. 2016 Dec 1;87(12):1031-1035. doi: 10.3357/AMHP.4571.2016. PubMed PMID: 28323589.

9: Dunna NR, Kandula V, Girdhar A, Pudutha A, Hussain T, Bandaru S, Nayarisseri A. High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma. Asian Pac J Cancer Prev. 2015;16(16):7089-95. PubMed PMID: 26514495.

10: Gao C, Grøtli M, Eriksson LA. Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase. J Mol Model. 2015 Jul;21(7):167. doi: 10.1007/s00894-015-2708-z. Epub 2015 Jun 6. PubMed PMID: 26044359.

11: Caglevic C, Grassi M, Raez L, Listi A, Giallombardo M, Bustamante E, Gil-Bazo I, Rolfo C. Nintedanib in non-small cell lung cancer: from preclinical to approval. Ther Adv Respir Dis. 2015 Aug;9(4):164-72. doi: 10.1177/1753465815579608. Epub 2015 Apr 7. Review. PubMed PMID: 25855060.

12: PLOS ONE Staff. Correction: challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience. PLoS One. 2015 Mar 26;10(3):e0121162. doi: 10.1371/journal.pone.0121162. eCollection 2015. PubMed PMID: 25811784; PubMed Central PMCID: PMC4374716.

13: Tebbutt N, Kotasek D, Burris HA, Schwartzberg LS, Hurwitz H, Stephenson J, Warner DJ, Chen L, Hsu CP, Goldstein D. Motesanib with or without panitumumab plus FOLFIRI or FOLFOX for the treatment of metastatic colorectal cancer. Cancer Chemother Pharmacol. 2015 May;75(5):993-1004. doi: 10.1007/s00280-015-2694-y. Epub 2015 Mar 15. PubMed PMID: 25772756.

14: Greenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budiman S, Devlin M, Street I, Adams TE, Johns TG. EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. Oncogene. 2015 Oct 8;34(41):5277-87. doi: 10.1038/onc.2014.448. Epub 2015 Feb 9. PubMed PMID: 25659577.

15: Gruber JJ, Colevas AD. Differentiated thyroid cancer: focus on emerging treatments for radioactive iodine-refractory patients. Oncologist. 2015 Feb;20(2):113-26. doi: 10.1634/theoncologist.2014-0313. Epub 2015 Jan 23. Review. PubMed PMID: 25616432; PubMed Central PMCID: PMC4319630.

16: Lkhoyaali S, Benhmida S, Ait Elhaj M, Layachi M, Bensouda Y, Errihani H. [Targeted therapy in thyroid cancer: Towards a treatment card]. Pathol Biol (Paris). 2015 Feb;63(1):1-6. doi: 10.1016/j.patbio.2014.11.003. Epub 2014 Dec 30. Review. French. PubMed PMID: 25555494.

17: Hong DS, Kurzrock R, Mulay M, Rasmussen E, Wu BM, Bass MB, Zhong ZD, Friberg G, Rosen LS. A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours. Oncotarget. 2014 Nov 30;5(22):11154-67. PubMed PMID: 25525888; PubMed Central PMCID: PMC4294348.

18: Bass MB, Yao B, Hei YJ, Ye Y, Davis GJ, Davis MT, Kaesdorf BA, Chan SS, Patterson SD. Challenges in developing a validated biomarker for angiogenesis inhibitors: the motesanib experience. PLoS One. 2014 Oct 14;9(10):e108048. doi: 10.1371/journal.pone.0108048. eCollection 2014. Erratum in: PLoS One. 2015;10(3):e0121162. PubMed PMID: 25314641; PubMed Central PMCID: PMC4196848.

19: Kim JG. Molecular pathogenesis and targeted therapies in well-differentiated thyroid carcinoma. Endocrinol Metab (Seoul). 2014 Sep;29(3):211-6. doi: 10.3803/EnM.2014.29.3.211. Review. PubMed PMID: 25309777; PubMed Central PMCID: PMC4192816.

20: Wang YJ, Zhang YK, Kathawala RJ, Chen ZS. Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance. Cancers (Basel). 2014 Sep 29;6(4):1925-52. doi: 10.3390/cancers6041925. Review. PubMed PMID: 25268163; PubMed Central PMCID: PMC4276951.



Additional Information

Motesanib is an orally-administered small molecule antagonist of vascular endothelial growth factor receptors 1, 2 and 3 (“VEGFR1-3”), platelet-derived growth factor receptor (“PDGFR”) and stem cell factor receptor (“c-kit”). It is being investigated as a cancer treatment. We are developing this product in collaboration with Takeda.