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].
References:
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[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)是一种口服多靶点酪氨酸激酶抑制剂，可抑制多种激酶，包括FLT3、KIT、PDGFR 和 VEGFR（IC50 = 22-500nM） [1-2]。Midostaurin竞争性地抑制ATP与激酶的结合，从而阻止肿瘤细胞增殖并促进细胞凋亡 [3]。Midostaurin常用于治疗携带FLT3突变的急性髓系白血病（AML） [4]。
在外周血单核细胞（PBMC）中，Midostaurin（1µM；72h）显著降低CD4+CD25+FOXP3+T细胞群和FOXP3 mRNA的表达 [5]。在MDA-MB-468细胞中，Midostaurin（1µM；72h）直接抑制Aurora激酶A和B，从而降低TNBC细胞的细胞活力 [6]。在HMC-1细胞中，普纳替尼与Midostaurin（0-0.1µM；48h）协同作用，导致生长抑制和细胞凋亡 [7]。
在CT26细胞异种移植瘤小鼠模型中，Midostaurin（100mg/kg；po；7d）治疗显著抑制肿瘤生长 [8]。在HL-60细胞异种移植瘤小鼠模型中，全反式维甲酸联合Midostaurin（50mg/kg；po；10d）治疗显著抑制肿瘤生长 [9]。