Midostaurin | PKC412 | CAS#120685-11-2 | PKCalpha inhibitor

MedKoo Cat#: 201850 | Name: Midostaurin

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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.

Chemical Structure

Midostaurin

CAS#120685-11-2

Theoretical Analysis

MedKoo Cat#: 201850

Name: Midostaurin

CAS#: 120685-11-2

Chemical Formula: C35H30N4O4

Exact Mass: 570.2267

Molecular Weight: 570.64

Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 400.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 1,050.00	Ready to ship
500mg	USD 2,250.00	2 Weeks
1g	USD 3,850.00	2 Weeks
2g	USD 6,150.00	2 Weeks

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Related CAS #

No Data

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# C8R11B02

QC Data

View QC data: current batch, Lot# C8R11B02

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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	mg/mL	mM
Solubility
	DMSO	43.1	75.60
	DMF	20.0	35.05
	Ethanol	2.0	3.50

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 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:

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.

1: Wang ES. Beyond midostaurin: Which are the most promising FLT3 inhibitors in AML? Best Pract Res Clin Haematol. 2019 Dec;32(4):101103. doi: 10.1016/j.beha.2019.101103. Epub 2019 Oct 18. Review. PubMed PMID: 31779982. 2: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548874/ PubMed PMID: 31644181. 3: Midostaurin for acute myeloid leukaemia, mastocytosis, and mast cell leukaemia. Aust Prescr. 2019 Apr;42(2):73-74. doi: 10.18773/austprescr.2019.017. Epub 2019 Feb 28. Review. PubMed PMID: 31048943; PubMed Central PMCID: PMC6478956. 4: Sly N, Gaspar K. Midostaurin for the management of FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis. Am J Health Syst Pharm. 2019 Feb 9;76(5):268-274. doi: 10.1093/ajhp/zxy050. Review. PubMed PMID: 30753289. 5: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Available from http://www.ncbi.nlm.nih.gov/books/NBK500909/ PubMed PMID: 29999968. 6: Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018 Feb 27;2(4):444-453. doi: 10.1182/bloodadvances.2017011080. Review. Erratum in: Blood Adv. 2018 Apr 10;2(7):787. PubMed PMID: 29487059; PubMed Central PMCID: PMC5858474. 7: Weisberg E, Sattler M, Manley PW, Griffin JD. Spotlight on midostaurin in the treatment of FLT3-mutated acute myeloid leukemia and systemic mastocytosis: design, development, and potential place in therapy. Onco Targets Ther. 2017 Dec 29;11:175-182. doi: 10.2147/OTT.S127679. eCollection 2018. Review. PubMed PMID: 29343975; PubMed Central PMCID: PMC5749544. 8: Garcia JS, Percival ME. Midostaurin for the treatment of adult patients with newly diagnosed acute myeloid leukemia that is FLT3 mutation-positive. Drugs Today (Barc). 2017 Oct;53(10):531-543. doi: 10.1358/dot.2017.53.10.2717625. Review. PubMed PMID: 29286055. 9: Kim M, Williams S. Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. Ann Pharmacother. 2018 Apr;52(4):364-369. doi: 10.1177/1060028017747900. Epub 2017 Dec 12. Review. PubMed PMID: 29231051. 10: Luskin MR, DeAngelo DJ. Midostaurin/PKC412 for the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia. Expert Rev Hematol. 2017 Dec;10(12):1033-1045. doi: 10.1080/17474086.2017.1397510. Epub 2017 Oct 30. Review. PubMed PMID: 29069942. 11: Gallogly MM, Lazarus HM, Cooper BW. Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Ther Adv Hematol. 2017 Sep;8(9):245-261. doi: 10.1177/2040620717721459. Epub 2017 Aug 19. Review. PubMed PMID: 29051803; PubMed Central PMCID: PMC5639976. 12: Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood. 2017 Dec 7;130(23):2469-2474. doi: 10.1182/blood-2017-08-784066. Epub 2017 Oct 19. Review. PubMed PMID: 29051180. 13: Stansfield LC, Pollyea DA. Midostaurin: A New Oral Agent Targeting FMS-Like Tyrosine Kinase 3-Mutant Acute Myeloid Leukemia. Pharmacotherapy. 2017 Dec;37(12):1586-1599. doi: 10.1002/phar.2039. Epub 2017 Nov 23. Review. PubMed PMID: 28976600. 14: Kayser S, Levis MJ, Schlenk RF. Midostaurin treatment in FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Expert Rev Clin Pharmacol. 2017 Nov;10(11):1177-1189. doi: 10.1080/17512433.2017.1387051. Epub 2017 Oct 10. Review. PubMed PMID: 28960095. 15: Valent P, Akin C, Hartmann K, George TI, Sotlar K, Peter B, Gleixner KV, Blatt K, Sperr WR, Manley PW, Hermine O, Kluin-Nelemans HC, Arock M, Horny HP, Reiter A, Gotlib J. Midostaurin: a magic bullet that blocks mast cell expansion and activation. Ann Oncol. 2017 Oct 1;28(10):2367-2376. doi: 10.1093/annonc/mdx290. Review. PubMed PMID: 28945834. 16: Kim ES. Midostaurin: First Global Approval. Drugs. 2017 Jul;77(11):1251-1259. doi: 10.1007/s40265-017-0779-0. Review. PubMed PMID: 28612232. 17: Patnaik MM. Midostaurin for the treatment of acute myeloid leukemia. Future Oncol. 2017 Sep;13(21):1853-1871. doi: 10.2217/fon-2017-0160. Epub 2017 Jun 14. Review. PubMed PMID: 28610444. 18: Levis M. Midostaurin approved for FLT3-mutated AML. Blood. 2017 Jun 29;129(26):3403-3406. doi: 10.1182/blood-2017-05-782292. Epub 2017 May 25. Review. PubMed PMID: 28546144. 19: Chandesris MO, Damaj G, Lortholary O, Hermine O. Clinical potential of midostaurin in advanced systemic mastocytosis. Blood Lymphat Cancer. 2017 May 3;7:25-35. doi: 10.2147/BLCTT.S87186. eCollection 2017. Review. PubMed PMID: 31360083; PubMed Central PMCID: PMC6467340. 20: Tvedt TH, Nepstad I, Bruserud Ø. Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells. Expert Opin Investig Drugs. 2017 Mar;26(3):343-355. doi: 10.1080/13543784.2017.1275564. Epub 2016 Dec 28. Review. PubMed PMID: 28001095.