Synonym
AZD3463; AZD 3463; AZD-3463.
IUPAC/Chemical Name
N-(4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine.
InChi Key
GCYIGMXOIWJGBU-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H25ClN6O/c1-32-22-12-16(31-10-8-15(26)9-11-31)6-7-21(22)29-24-28-14-19(25)23(30-24)18-13-27-20-5-3-2-4-17(18)20/h2-7,12-15,27H,8-11,26H2,1H3,(H,28,29,30)
SMILES Code
ClC1=CN=C(NC2=CC=C(N3CCC(N)CC3)C=C2OC)N=C1C4=CNC5=C4C=CC=C5
Appearance
Light green to green 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:
AZD-3463 (ALK/IGF1R inhibitor) is an ALK/IGF1R inhibitor, with a Ki of 0.75 nM for ALK.
In vitro activity:
Wild-type FLT3 is required for normal hematopoiesis. Therefore, inhibition of wild-type FLT3 is likely to cause unwanted side effects. For this reason, this study checked whether AZD3463 also inhibits wild-type FLT3 signaling. Ligand-induced activation of FLT3 results in activation of AKT and ERK1/2 signaling. In contrast, FLT3-ITD is constitutively active and activates downstream signaling cascades. This study observed that treatment with AZD3463 inhibited FLT3-ITD-mediated activation of AKT, ERK1/2, and p38 in a dose-dependent manner in MOLM-13 cells (Fig. 2a) as well as in MV4-11 cells (Fig. 5SA). Tyrosine phosphorylation of FLT3 was also reduced in a similar fashion (Fig. 2A and Fig. S5A). Both MOLM-13 and MV4-11 carry an FLT3-ITD mutation, but MOLM-13 cells also express one copy of wild-type FLT3. However, AZD3463 did not affect FL-stimulated tyrosine phosphorylation of FLT3 or its downstream signaling in MOLM-13 cells (Fig. 2a and Fig. S5B), in Ba/F3 cells transfected with FLT3-WT (Fig. 2b) or in THP-1 cells (expressing wild-type FLT3; Fig. S5C) suggesting that AZD3463 selectively inhibits oncogenic FLT3-ITD but not wild-type FLT3.
Reference: Blood Cancer J. 2019 Feb; 9(2): 5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333797/
In vivo activity:
Significant tumor growth inhibition was observed in both AZD3463 treatment groups (SH-SY5Y and NGP) compared with the control groups. Treatment in SH-SY5Y xenograft mice with AZD3463 resulted in almost complete tumor regression and significant regression was observed in NGP xenograft mice (Fig. 5A,C). After the mice had been bearing the SH-SY5Y and NGP tumors for 4 weeks, the mice were treated with either AZD3463 or DMSO via intraperitoneal injection for 48 hours. Then this study examined the effect of AZD3463 on the PI3K/AKT/mTOR signaling in the tumor tissues and found that AZD3463 efficiently blocked Akt and RPS6 phosphorylation and induced the cleavage of PARP, caspase 3, and LC3 A/BΙΙ (Fig. 5E) in vivo. These results suggest that AZD3463 can effectively induce apoptosis and autophagy as a single agent in orthotopic xenograft mouse models of NB.
Reference: Sci Rep. 2016; 6: 19423. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726162/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
9.8 |
21.76 |
|
| DMF |
2.5 |
5.57 |
|
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
448.95
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. Moharram SA, Shah K, Khanum F, Rönnstrand L, Kazi JU. The ALK inhibitor AZD3463 effectively inhibits growth of sorafenib-resistant acute myeloid leukemia. Blood Cancer J. 2019 Jan 15;9(2):5. doi: 10.1038/s41408-018-0169-1. Erratum in: Blood Cancer J. 2019 Jul 25;9(8):54. PMID: 30647405; PMCID: PMC6333797.
2. Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC, Huang SL, Akiyama Y, Yang Y, Sun W, Xu X, Shi Y, Zhang H, Kim ES, Muscal JA, Lu F, Yang J. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423. PMID: 26786851; PMCID: PMC4726162.
In vitro protocol:
1. Moharram SA, Shah K, Khanum F, Rönnstrand L, Kazi JU. The ALK inhibitor AZD3463 effectively inhibits growth of sorafenib-resistant acute myeloid leukemia. Blood Cancer J. 2019 Jan 15;9(2):5. doi: 10.1038/s41408-018-0169-1. Erratum in: Blood Cancer J. 2019 Jul 25;9(8):54. PMID: 30647405; PMCID: PMC6333797.
2. Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC, Huang SL, Akiyama Y, Yang Y, Sun W, Xu X, Shi Y, Zhang H, Kim ES, Muscal JA, Lu F, Yang J. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423. PMID: 26786851; PMCID: PMC4726162.
In vivo protocol:
1. Hu GF, Wang C, Hu GX, Wu G, Zhang C, Zhu W, Chen C, Gu Y, Zhang H, Yang Z. AZD3463, an IGF-1R inhibitor, suppresses breast cancer metastasis to bone via modulation of the PI3K-Akt pathway. Ann Transl Med. 2020 Mar;8(6):336. doi: 10.21037/atm.2020.02.110. PMID: 32355780; PMCID: PMC7186597.
2. Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC, Huang SL, Akiyama Y, Yang Y, Sun W, Xu X, Shi Y, Zhang H, Kim ES, Muscal JA, Lu F, Yang J. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423. PMID: 26786851; PMCID: PMC4726162.
1: Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC,
Huang SL, Akiyama Y, Yang Y, Sun W, Xu X, Shi Y, Zhang H, Kim ES, Muscal JA, Lu
F, Yang J. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by
overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 2016 Jan
20;6:19423. doi: 10.1038/srep19423. PubMed PMID: 26786851; PubMed Central PMCID:
PMC4726162.
2: Sampson VB, Vetter NS, Kamara DF, Collier AB, Gresh RC, Kolb EA. Vorinostat
Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and
Activates STAT3/AKT/MAPK Pathways. PLoS One. 2015 Nov 16;10(11):e0142704. doi:
10.1371/journal.pone.0142704. PubMed PMID: 26571493; PubMed Central PMCID:
PMC4646493.
