Synonym
AMG900; AMG-900; AMG 900.
IUPAC/Chemical Name
N-(4-((3-(2-aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine.
InChi Key
IVUGFMLRJOCGAS-UHFFFAOYSA-N
InChi Code
InChI=1S/C28H21N7OS/c1-17-15-24(37-16-17)25-20-5-2-3-6-21(20)26(35-34-25)32-18-8-10-19(11-9-18)36-27-22(7-4-13-30-27)23-12-14-31-28(29)33-23/h2-16H,1H3,(H,32,35)(H2,29,31,33)
SMILES Code
CC1=CSC(C2=NN=C(NC3=CC=C(OC4=NC=CC=C4C5=NC(N)=NC=C5)C=C3)C6=C2C=CC=C6)=C1
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
>5 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
More Info
MG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser10, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes. (Source: Cancer Res; 70(23); 9846–54.)
Biological target:
AMG 900 is a pan-Aurora kinases inhibitor with IC50 of 5 nM, 4 nM and 1 nM for Aurora A, B and C, respectively.
In vitro activity:
Treatment with AMG900 reduced growth of A172, U‐87MG, and U‐118MG cells in a concentration‐dependent manner (from 0.1 to 100 nmol/L; Figure 1A). In addition, while the number of DMSO‐treated control cells increased in a time‐dependent manner (from 24 to 120 hours), this was not the case for 100 nmol/L AMG900‐treated cells (Figure 1B). To examine the long‐term effects of AMG900, we exposed A172 cells to AMG900 for 24 hours, washed out drug, and examined colony formation after 14 days. AMG900‐treated cells showed significantly lower colony‐forming activity than control cells (Figure 1C), suggesting that short‐term exposure results in irreversible defects in survival. Overall, the data indicate that AMG900 reduces the proliferation of glioblastoma cells.
Reference: Cancer Med. 2018 Nov; 7(11): 5589–5603. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246935/
In vivo activity:
As measured by whole body bioluminescence, mice treated with AMG 900 using either dose schedule showed significant anti-tumor activity across study time points relative to vehicle-treated group [tumor growth inhibition 86–90% and 94%, P < .0001 (days 6 and 9); 95%, P < 0.02 (day 12)] (Fig. 5B). Relative to vehicle-treated group, AMG 900 significantly reduced the MOLM-13 cell fraction in the marrow (P ≤ 0.0002) (Fig. 5D), with 7-day schedule reducing tumor burden to a greater degree than the 4-day schedule (P = 0.0152).
Reference: Mol Cancer Ther. 2018 Dec; 17(12): 2575–2585. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279493/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
55.0 |
109.22 |
| DMF |
15.0 |
29.79 |
| DMF:PBS (pH 7.2) (1:3) |
0.3 |
0.50 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
503.58
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.
| 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. Ryu J, Pyo J, Lee CW, Kim JE. An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression. Cancer Med. 2018 Nov;7(11):5589-5603. doi: 10.1002/cam4.1771. Epub 2018 Sep 17. PMID: 30221846; PMCID: PMC6246935.
2. Borges KS, Andrade AF, Silveira VS, Marco Antonio DS, Vasconcelos EJR, Antonini SRR, Tone LG, Scrideli CA. The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line. Anticancer Drugs. 2017 Jul;28(6):634-644. doi: 10.1097/CAD.0000000000000504. PMID: 28410270.
3. Payton M, Cheung HK, Ninniri MSS, Marinaccio C, Wayne WC, Hanestad K, Crispino JD, Juan G, Coxon A. Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes. Mol Cancer Ther. 2018 Dec;17(12):2575-2585. doi: 10.1158/1535-7163.MCT-18-0186. Epub 2018 Sep 28. PMID: 30266802; PMCID: PMC6279493.
4. Juan G, Bush TL, Ma C, Manoukian R, Chung G, Hawkins JM, Zoog S, Kendall R, Radinsky R, Loberg R, Friberg G, Payton M. AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues. J Transl Med. 2014 Nov 4;12:307. doi: 10.1186/s12967-014-0307-x. PMID: 25367255; PMCID: PMC4221688.
In vitro protocol:
1. Ryu J, Pyo J, Lee CW, Kim JE. An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression. Cancer Med. 2018 Nov;7(11):5589-5603. doi: 10.1002/cam4.1771. Epub 2018 Sep 17. PMID: 30221846; PMCID: PMC6246935.
2. Borges KS, Andrade AF, Silveira VS, Marco Antonio DS, Vasconcelos EJR, Antonini SRR, Tone LG, Scrideli CA. The aurora kinase inhibitor AMG 900 increases apoptosis and induces chemosensitivity to anticancer drugs in the NCI-H295 adrenocortical carcinoma cell line. Anticancer Drugs. 2017 Jul;28(6):634-644. doi: 10.1097/CAD.0000000000000504. PMID: 28410270.
In vivo protocol:
1. Payton M, Cheung HK, Ninniri MSS, Marinaccio C, Wayne WC, Hanestad K, Crispino JD, Juan G, Coxon A. Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes. Mol Cancer Ther. 2018 Dec;17(12):2575-2585. doi: 10.1158/1535-7163.MCT-18-0186. Epub 2018 Sep 28. PMID: 30266802; PMCID: PMC6279493.
2. Juan G, Bush TL, Ma C, Manoukian R, Chung G, Hawkins JM, Zoog S, Kendall R, Radinsky R, Loberg R, Friberg G, Payton M. AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues. J Transl Med. 2014 Nov 4;12:307. doi: 10.1186/s12967-014-0307-x. PMID: 25367255; PMCID: PMC4221688.
1: Waldon D, Berry L, Lin MH, Schenkel L, Hollis LS, Zhao Z. Gender Effects on Rat Metabolism of AMG 900, an Orally Available Small Molecule Aurora Kinase Inhibitor. Drug Metab Lett. 2011 Oct 21. [Epub ahead of print] PubMed PMID: 22022868.
2: Huang L, Be X, Berry L, Moore E, Janosky B, Wells M, Pan WJ, Zhao Z, Lin MH. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. Xenobiotica. 2011 May;41(5):400-8. Epub 2011 Feb 4. PubMed PMID: 21294625.
3: Payton M, Bush TL, Chung G, Ziegler B, Eden P, McElroy P, Ross S, Cee VJ, Deak HL, Hodous BL, Nguyen HN, Olivieri PR, Romero K, Schenkel LB, Bak A, Stanton M, Dussault I, Patel VF, Geuns-Meyer S, Radinsky R, Kendall RL. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010 Dec 1;70(23):9846-54. Epub 2010 Oct 8. PubMed PMID: 20935223.
