WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406211
CAS#: 630124-46-8
Description: AST487, also known as NVP-AST487, is a RET kinase inhibitor/FLT3 inhibitor. The RET kinase has emerged as a promising target for the therapy of medullary thyroid cancers (MTC) and of a subset of papillary thyroid cancers. NVP- AST487 has an IC(50) of 0.88 mumol/L on RET kinase, inhibits RET autophosphorylation and activation of downstream effectors, and potently inhibited the growth of human thyroid cancer cell lines with activating mutations of RET but not of lines without RET mutations. NVP- AST487 induced a dose-dependent growth inhibition of xenografts of NIH3T3 cells expressing oncogenic RET, and of the MTC cell line TT in nude mice. NVP- AST487 inhibited calcitonin gene expression in vitro in TT cells, in part, through decreased gene transcription.
MedKoo Cat#: 406211
Name: AST487
CAS#: 630124-46-8
Chemical Formula: C26H30F3N7O2
Exact Mass: 529.24131
Molecular Weight: 529.56
Elemental Analysis: C, 58.97; H, 5.71; F, 10.76; N, 18.51; O, 6.04
Synonym: NVP AST487; NVP AST-487; NVP AST 487; NVP-AST487; NVP-AST-487; NVP-AST 487; AST 487; AST487; AST-487.
IUPAC/Chemical Name: 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)urea
InChi Key: ODPGGGTTYSGTGO-UHFFFAOYSA-N
InChi Code: InChI=1S/C26H30F3N7O2/c1-3-35-10-12-36(13-11-35)16-18-4-5-20(14-22(18)26(27,28)29)34-25(37)33-19-6-8-21(9-7-19)38-24-15-23(30-2)31-17-32-24/h4-9,14-15,17H,3,10-13,16H2,1-2H3,(H,30,31,32)(H2,33,34,37)
SMILES Code: O=C(NC1=CC=C(OC2=NC=NC(NC)=C2)C=C1)NC3=CC=C(CN4CCN(CC)CC4)C(C(F)(F)F)=C3
Appearance: 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: >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
| Biological target: | AST 487 is a RET kinase inhibitor with IC50 of 880 nM, inhibits RET autophosphorylation and activation of downstream effectors, also inhibits Flt-3 with IC50 of 520 nM. |
| In vitro activity: | Treatment of FLT3-ITD-Ba/F3 cells and D835Y-Ba/F3 cells with NVP-AST487 potently inhibited cellular proliferation (IC50 < .005 μM; Figure 1B,C). Supplementation of culture media with WEHI, used as a source of IL-3, led to rescue of the cells, suggesting that NVP-AST487 selectively inhibits FLT3-ITD and has no effect on IL-3 signaling. The antiproliferative activity of NVP-AST487 was not blunted by addition of human serum (Figure S3). Cells expressing the novel point mutant FLT3-N841I also showed sensitivity to NVP-AST487 (Figure S1). Parental Ba/F3 cells were not affected by up to 0.1 μM NVP-AST487 (Figure 1B). Similarly, the results of a CFU-GM colony formation assay showed no toxicity of human bone marrow progenitor cells at concentrations up to 0.1 μM NVP-AST487 (Figure 1D). A dose-dependent increase of apoptotic cells was observed in FLT-ITD-Ba/F3 cells cultured in the presence of NVP-AST487 (at concentrations up to 0.1 μM; Figure 4A). Viability of cells cultured in the presence of the inhibitor in media supplemented with IL-3 was preserved following 3 days of treatment (Figure 4A). Induction of apoptosis was similarly observed in D835Y-Ba/F3 cells treated for 3 days in the presence of NVP-AST487 at concentrations of 0.01 μM and 0.1 μM (Figure 4B). There was no apparent induction of apoptosis of parental Ba/F3 cells cultured with IL-3 in the presence of NVP-AST487 for the same length of time (Figure 4C). Reference: Blood. 2008 Dec 15;112(13):5161-70. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18820131/ |
| In vivo activity: | The ability of the inhibitor, NVP-AST487, to inhibit proliferation of mutant FLT3-expressing cells in vivo was investigated using athymic nude mice that had been inoculated with FLT3-ITD-Ba/F3 cells via tail-vein injection. Mice were orally administered vehicle (10% NMP-90% PEG300), 30 mg/kg NVP-AST487 (“low-dose” NVP-AST487), or 50 mg/kg NVP-AST487 (“high-dose” NVP-AST487) for a total of 21 days by gavage. Drug was not administered on weekends. All vehicle-treated mice died after 24 days following initial injection of the FLT3-ITD-Ba/F3 cells, whereas the majority of NVP-AST487–treated mice (at both doses) survived up to day 29 (Figure 6A). Median survival for vehicle control mice was 20 days; median for low- and high-dose mice was 30 days. The survival was different among the 3 groups (P < .001). Vehicle control mice died sooner than the low-dose-treated mice (P < .001) and sooner than the high-dose-treated mice (P = .005). There was no significant difference in survival between the low- and high-dose mice (P = .70). Reference: Blood. 2008 Dec 15;112(13):5161-70. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18820131/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 100.0 | 188.84 | |
| Ethanol | 33.0 | 62.32 |
The following data is based on the product molecular weight 529.56 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 |
| In vitro protocol: | 1. Weisberg E, Roesel J, Bold G, Furet P, Jiang J, Cools J, Wright RD, Nelson E, Barrett R, Ray A, Moreno D, Hall-Meyers E, Stone R, Galinsky I, Fox E, Gilliland G, Daley JF, Lazo-Kallanian S, Kung AL, Griffin JD. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells. Blood. 2008 Dec 15;112(13):5161-70. doi: 10.1182/blood-2008-02-138065. Epub 2008 Sep 26. PMID: 18820131; PMCID: PMC2597611. 2. Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R, Caravatti G, Fabbro D, Lane HA, Fagin JA. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007 Jul 15;67(14):6956-64. doi: 10.1158/0008-5472.CAN-06-4605. PMID: 17638907. |
| In vivo protocol: | 1. Weisberg E, Roesel J, Bold G, Furet P, Jiang J, Cools J, Wright RD, Nelson E, Barrett R, Ray A, Moreno D, Hall-Meyers E, Stone R, Galinsky I, Fox E, Gilliland G, Daley JF, Lazo-Kallanian S, Kung AL, Griffin JD. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells. Blood. 2008 Dec 15;112(13):5161-70. doi: 10.1182/blood-2008-02-138065. Epub 2008 Sep 26. PMID: 18820131; PMCID: PMC2597611. 2. Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R, Caravatti G, Fabbro D, Lane HA, Fagin JA. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007 Jul 15;67(14):6956-64. doi: 10.1158/0008-5472.CAN-06-4605. PMID: 17638907. |
1: Weisberg E, Roesel J, Furet P, Bold G, Imbach P, Flörsheimer A, Caravatti G, Jiang J, Manley P, Ray A, Griffin JD. Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors: Structure-Affinity Comparison. Genes Cancer. 2010 Oct;1(10):1021-32. doi: 10.1177/1947601910396505. PubMed PMID: 21779428; PubMed Central PMCID: PMC3092267.
2: Weisberg E, Roesel J, Bold G, Furet P, Jiang J, Cools J, Wright RD, Nelson E, Barrett R, Ray A, Moreno D, Hall-Meyers E, Stone R, Galinsky I, Fox E, Gilliland G, Daley JF, Lazo-Kallanian S, Kung AL, Griffin JD. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells. Blood. 2008 Dec 15;112(13):5161-70. doi: 10.1182/blood-2008-02-138065. Epub 2008 Sep 26. PubMed PMID: 18820131; PubMed Central PMCID: PMC2597611.
3: Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R, Caravatti G, Fabbro D, Lane HA, Fagin JA. The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007 Jul 15;67(14):6956-64. PubMed PMID: 17638907.
