WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H201850
CAS#: 120685-11-2
Description: Midostaurin, also known as PKC-412, PKC-412A and CGP 41251; is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors. Midostaurin was approved in 2017.
Hodoodo Cat#: H201850
Name: Midostaurin
CAS#: 120685-11-2
Chemical Formula: C35H30N4O4
Exact Mass: 570.23
Molecular Weight: 570.637
Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22
Synonym: PKC-412; PKC412; PKC 412; PKC412A; PKC-412A; PKC 412A; CGP41251; CGP 41251; CGP-41251; Midostaurin; Rydapt
IUPAC/Chemical Name: N-((5R,7R,8R,9S)-8-methoxy-9-methyl-16-oxo-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b,h]cyclonona[jkl]cyclopenta[e]-as-indacen-7-yl)-N-methylbenzamide
InChi Key: BMGQWWVMWDBQGC-IIFHNQTCSA-N
InChi Code: InChI=1S/C35H30N4O4/c1-35-32(42-3)25(37(2)34(41)19-11-5-4-6-12-19)17-26(43-35)38-23-15-9-7-13-20(23)28-29-22(18-36-33(29)40)27-21-14-8-10-16-24(21)39(35)31(27)30(28)38/h4-16,25-26,32H,17-18H2,1-3H3,(H,36,40)/t25-,26-,32-,35+/m1/s1
SMILES Code: C[C@@]12[C@H](OC)[C@H](N(C(C3=CC=CC=C3)=O)C)C[C@H](N4C5=CC=CC=C5C6=C7C(CNC7=O)=C8C9=CC=CC=C9N2C8=C64)O1
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 soluble 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:
| Biological target: | Midostaurin (PKC412; CGP 41251) is a multi-targeted protein kinase inhibitor which inhibits PKCα/β/γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ and VEGFR1/2 with IC50s ranging from 22-500 nM. |
| In vitro activity: | To better understand the mechanism of midostaurin against AML cells expressing either mutated or wt FLT3, its effects on signalling molecules, including those implicated in inhibiting apoptosis as well as those contributing to cellular transformation, were examined. Consistent with the characterization of midostaurin as pro-apoptotic, at a concentration of 100 nmol/L, midostaurin, in a time-dependent manner, decreased levels of Mcl-1 and Bcl-xL in mutant FLT3-expressing Ba/F3 and MOLM14 cells, with effects apparent within 24 hours (Figures 2A and S1A). For wt FLT3-expressing Kasumi-1-luc+ cells and OCI-AML2 cells, midostaurin modestly decreased levels of Bcl-xL, however not Mcl-1, at 250 nmol/L following 2 days of treatment (Figure 2B,C). Down-regulation of Bcl-xL by midostaurin correlated with induction of apoptosis in both cell lines (Figures 2D and B,C). Midostaurin inhibited phosphorylation of key mediators of PI3K/AKT and MAPK signalling, including AKT, S6 and MAPK, in a concentration-dependent manner in wt FLT3-expressing Kasumi-1-luc+ cells, with strong suppression of S6 and MAPK phosphorylation observed at 125 nmol/L and no effects on total AKT, S6 and MAPK protein levels (Figures and S1D-F). The utility of pS6 as a biomarker for the efficacy of midostaurin against wt FLT3-expressing AML was investigated by comparing drug effects on pS6 in AML cell lines that were around 2-fold or more sensitive to midostaurin (Kasumi-1-luc+, K052, OCI-AML2) than other AML cell lines (HEL, OCI-AML3). A decrease in pS6 was observed in midostaurin-treated Kasumi-1-luc+, K052 and OCI-AML2 at concentrations 250-500 nmol/L (Figure 2F). In contrast, there was no decrease in pS6 in HEL or OCI-AML3 cells treated at the same concentrations (Figure 2F). These results suggest that pS6 is a good biomarker for midostaurin activity and reflect the inhibition of MAPK signalling by midostaurin as a key component of its mechanism. Reference: J Cell Mol Med. 2020 Mar;24(5):2968-2980. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077552/ |
| In vivo activity: | An OCI-AML3-luc+ xenograft model was also utilized to measure the in vivo efficacy of midostaurin; OCI-AML3-luc+ cells express NRAS Q61L and carry an NPM1 gene mutation (type A) and the DNMT3A R882C mutation. Midostaurin significantly lowered leukaemia burden as a function of bioluminescence in mice (P < .0001 for SKNO-1-luc+ xenograft model and P < .0001 for OCI-AML3-luc+ xenograft model) (Figures 4A,D and S2B), and significantly increased median survival (P < .0001 for SKNO-1-luc+ xenograft model and P < .0001 for OCI-AML3-luc+ xenograft model) (Figure 4B,E). Representative mouse images for vehicle control and midostaurin treatment groups are shown in Figures 4C,F and S3. Midostaurin was well-tolerated at 80 mg/kg in the SKNO-1-luc+ xenograft model and at 100 mg/kg in the OCI-AML3-luc+ xenograft model (Figure S2C,D). Taken together, these data suggest that wt FLT3‐expressing AML cells can be efficiently targeted in vivo by midostaurin. Reference: J Cell Mol Med. 2020 Mar;24(5):2968-2980. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077552/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 43.1 | 75.60 | |
| DMF | 20.0 | 35.05 | |
| Ethanol | 2.0 | 3.50 |
The following data is based on the product molecular weight 570.64 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. Ji N, Yang Y, Cai CY, Wang JQ, Lei ZN, Wu ZX, Cui Q, Yang DH, Chen ZS, Kong D. Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study. Front Oncol. 2019 Jun 18;9:514. doi: 10.3389/fonc.2019.00514. PMID: 31275850; PMCID: PMC6591272. 2. Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, Yang J, Liu X, Wang J, Gray N, Adamia S, Sattler M, Stone R, Griffin JD. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med. 2020 Mar;24(5):2968-2980. doi: 10.1111/jcmm.14927. Epub 2020 Jan 22. PMID: 31967735; PMCID: PMC7077552. 3. Ge X, Chen J, Li L, Ding P, Wang Q, Zhang W, Li L, Lv X, Zhou D, Jiang Z, Zeng H, Xu Y, Hou Y, Hu W. Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis. Cell Death Dis. 2018 Dec 18;10(1):8. doi: 10.1038/s41419-018-1259-5. PMID: 30584254; PMCID: PMC6315025. |
| In vitro protocol: | 1. Ji N, Yang Y, Cai CY, Wang JQ, Lei ZN, Wu ZX, Cui Q, Yang DH, Chen ZS, Kong D. Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study. Front Oncol. 2019 Jun 18;9:514. doi: 10.3389/fonc.2019.00514. PMID: 31275850; PMCID: PMC6591272. 2. Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, Yang J, Liu X, Wang J, Gray N, Adamia S, Sattler M, Stone R, Griffin JD. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med. 2020 Mar;24(5):2968-2980. doi: 10.1111/jcmm.14927. Epub 2020 Jan 22. PMID: 31967735; PMCID: PMC7077552. |
| In vivo protocol: | 1. Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, Yang J, Liu X, Wang J, Gray N, Adamia S, Sattler M, Stone R, Griffin JD. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med. 2020 Mar;24(5):2968-2980. doi: 10.1111/jcmm.14927. Epub 2020 Jan 22. PMID: 31967735; PMCID: PMC7077552. 2. Ge X, Chen J, Li L, Ding P, Wang Q, Zhang W, Li L, Lv X, Zhou D, Jiang Z, Zeng H, Xu Y, Hou Y, Hu W. Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis. Cell Death Dis. 2018 Dec 18;10(1):8. doi: 10.1038/s41419-018-1259-5. PMID: 30584254; PMCID: PMC6315025. |
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