- 貨號: ajci5234
- CAS: 120685-11-2
- 別名: 米哚妥林; PKC412; CGP 41251
- 分子式: C35H30N4O4
- 分子量: 570.64
- 純度: ＞98%
- 溶解度: ≥ 57.1mg/mL in DMSO with ultrasonic
- 儲存: Store at -20°C
- 庫存: 現貨
Background
Midostaurin (PKC412) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits multiple kinases, including FLT3, KIT, PDGFR, and VEGFR (IC50 = 22-500nM) [1-2]. Midostaurin competitively inhibits the binding of ATP to kinases, thereby blocking tumor cell proliferation and promoting apoptosis [3]. Midostaurin is commonly used to treat acute myeloid leukemia (AML) harboring FLT3 mutations [4].
In peripheral blood mononuclear cells (PBMCs), Midostaurin (1μM; 72h) significantly reduced the CD4+CD25+FOXP3+ T cell population and FOXP3 mRNA expression in PBMCs [5]. In MDA -MB-468 cells, Midostaurin (1μM; 72h) directly inhibits Aurora kinases A and B and subsequently reduces cell viability in TNBC cells [6]. In HMC-1 cells, ponatinib cooperates with Midostaurin (0-0.1μM; 48h) to induce growth inhibition and apoptosis [7].
In CT26 cells xenograft tumor mouse model, Midostaurin (100mg/kg; po; 7d) treatment significantly inhibited tumor growth [8]. In HL-60 cells xenograft tumor mouse model, All-trans retinoic acid combined with Midostaurin (50mg/kg; po; 10d) treatment significantly inhibited tumor growth [9].
參考文獻:
[1]. Fabbro D, Buchdunger E, Wood J, et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent[J]. Pharmacology & therapeutics, 1999, 82(2-3): 293-301.
[2]. Fabbro D, Ruetz S, Bodis S, et al. PKC412-a protein kinase inhibitor with a broad therapeutic potential[J]. Anti-cancer drug design, 2000, 15(1): 17-28.
[3]. Gallogly M M, Lazarus H M, Cooper B W. Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis[J]. Therapeutic advances in hematology, 2017, 8(9): 245-261.
[4]. Levis M. Midostaurin approved for FLT3-mutated AML[J]. Blood, The Journal of the American Society of Hematology, 2017, 129(26): 3403-3406.
[5]. Gutierrez L, Jang M, Zhang T, et al. Midostaurin reduces regulatory T cells markers in acute myeloid leukemia[J]. Scientific reports, 2018, 8(1): 17544.
[6]. Kawai M, Nakashima A, Kamada S, et al. Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family[J]. Journal of biomedical science, 2015, 22(1): 48.
[7]. Gleixner K V, Peter B, Blatt K, et al. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V[J]. Haematologica, 2013, 98(9): 1450.
[8]. Lai C T, Chi C W, Wu S H, et al. Midostaurin modulates tumor microenvironment and enhances efficacy of anti-PD-1 against colon cancer[J]. Cancers, 2022, 14(19): 4847.
[9]. Lu H, Weng X, Sheng Y, et al. Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3[J]. BMC cancer, 2022, 22(1): 749.
Midostaurin (PKC412)是一種口服多靶點酪氨酸激酶抑制劑，可抑制多種激酶，包括FLT3、KIT、PDGFR 和 VEGFR（IC50 = 22-500nM） [1-2]。Midostaurin競爭性地抑制ATP與激酶的結合，從而阻止腫瘤細胞增殖并促進細胞凋亡 [3]。Midostaurin常用于治療攜帶FLT3突變的急性髓系白血病（AML） [4]。
在外周血單核細胞（PBMC）中，Midostaurin（1μM；72h）顯著降低CD4+CD25+FOXP3+T細胞群和FOXP3 mRNA的表達 [5]。在MDA-MB-468細胞中，Midostaurin（1μM；72h）直接抑制Aurora激酶A和B，從而降低TNBC細胞的細胞活力 [6]。在HMC-1細胞中，普納替尼與Midostaurin（0-0.1μM；48h）協同作用，導致生長抑制和細胞凋亡 [7]。
在CT26細胞異種移植瘤小鼠模型中，Midostaurin（100mg/kg；po；7d）治療顯著抑制腫瘤生長 [8]。在HL-60細胞異種移植瘤小鼠模型中，全反式維甲酸聯合Midostaurin（50mg/kg；po；10d）治療顯著抑制腫瘤生長 [9]。
Protocol
| Cell experiment [1]: | |
Cell lines | Peripheral blood mononuclear cells (PBMCs) |
Preparation Method | PBMCs were cultured in Roswell Park Memorial Institute 1640 1x (RPMI) medium supplemented with 20% fetal bovine serum (FBS). In addition, PBMCs were treated with IL-2 (5ng/mL) and IL-7 (10ng/mL), as well as 1μM of Midostaurin. PBMCs were seeded at 2 million cells per well in a 6 well plate, and allowed to incubate at 5% CO2, 37?℃ for 72?hours before analysis via flow cytometry or quantitative polymerase chain reaction. |
Reaction Conditions | 1μM; 72h |
Applications | Midostaurin reduces CD4?+?CD25?+?FOXP3?+ T cell population in healthy PBMC. |
| Animal experiment [2]: | |
Animal models | CT26 cells xenograft tumor mouse model |
Preparation Method | Male BALB/c mice at five weeks old were purchased from the National Laboratory Animal Center of Taiwan and housed under 12-h light/dark cycle under a specific pathogen-free facility. The 4 × 106 CT26 cells in 100μL PBS were subcutaneously inoculated on the right hindlimb of the mice. After the tumors grew for 7 days to achieve a mean diameter of approximate 5mm, mice were randomly allocated into 4 groups as follows: (1) control, (2) Midostaurin (100mg/kg), (3) intraperitoneal anti-PD-1 injection (200μg), and (4) Midostaurin in combination with anti-PD-1. |
Dosage form | 100mg/kg; po; 7d |
Applications | Midostaurin treatment significantly inhibited tumor growth. |
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