Abstract：Acute myeloid leukemia (AML) is a malignant clonal disease with the characteristic of heterogeneity. Fms-like tyrosine kinase 3 (FLT3) belongs to the class III receptor tyrosine kinase, which promotes proliferation of hematopoietic cells and lymphocytes. Dysregulation of FLT3 was closely related to the occurrence and development of numerous tumors including AML. Thus, small molecule kinase inhibitors targeting FLT3 provided a promising treatment for cancer. However, primary and secondary drug resistance led to transient clinical responses. In order to seek a better way to treat drug-resistant AML, the advances of targeted therapy of small molecular FLT3 inhibitors for drug-resistant AML in recent five years were summarized in this review. The targeted therapy mainly included dual inhibitors targeted FLT3 and other kinases, irreversible FLT3 inhibitors, combination of FLT3 and other drugs, and FLT3-PROTAC, etc.
何欢, 徐兴伟, 宫帼唯, 祁宝辉. 小分子FLT3抑制剂用于耐药性急性髓系白血病靶向治疗的研究进展[J]. 中国药学杂志, 2020, 55(21): 1757-1761.
HE Huan, XU Xing-wei, GONG Guo-wei, QI Bao-hui. Advances of Targeted Therapy of Small Molecular FLT3 Inhibitors for Drug Resistance of Acute Myeloid Leukemia. Chinese Pharmaceutical Journal, 2020, 55(21): 1757-1761.
KENINS L, GILL J W, HOLLANDER G A, et al. Flt3 ligand-receptor interaction is important for maintenance of early thymic progenitor numbers in steady-state thymopoiesis [J]. Eur J Immunol, 2010, 40 (1):81-90.
[2]
CHENG J, QU J, WANG J, et al. High expression of FLT3 is a risk factor in leukemia [J]. Mol Med Rep, 2018, 17 (2):2885-2892.
[3]
POUBEL C P, MANSUR M B, BORONI M, et al. FLT3 overexpression in acute leukaemias: new insights into the search for molecular mechanisms [J]. BBA Rev Cancer, 2019, 1872 (1):80-88.
[4]
WU M, LI C, ZHU X. FLT3 inhibitors in acute myeloid leukemia [J]. J Hematol Oncol, 2018, 11: 133-143.
[5]
KAZI J U, RÖNNSTRAND L. FMS-LIKE tyrosine kinase 3/FLT3: from basic science to clinical implications[J]. Physiol Rev, 2019, 99 (3):1433-1466.
[6]
ZHOU J, CHNG W J. Resistance to FLT3 inhibitors in acute myeloid leukemia: molecular mechanisms and resensitizing strategies [J]. World J Clin Oncol, 2018, 9 (5):90-97.
[7]
TALLIS E, BORTHAKUR G. Novel treatments for relapsed/refractory acute myeloid leukemia with FLT3 mutations [J]. Expert Rev Hematol, 2019, 12 (8):621-640.
[8]
SAITO Y, UCHIDA N, TANAKA S, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML [J]. Nat Biotechnol, 2010, 28 (3):275-280.
[9]
KODA Y, KIKUZATO K, MIKUNI J, et al. Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors [J]. Bioorg Med Chem Lett, 2017, 27 (22):4994-4998.
[10]
BARBACID M, ORTEGA S, SOTILLO R, et al. Cell cycle and cancer: genetic analysis of the role of cyclin-dependent kinases [J]. Cold Spring Harb Symp Quant Biol, 2005, 70: 233-240.
[11]
SANTAMARIA D, ORTEGA S. Cyclins and CDKs in development and cancer: lessons from genetically modified mice [J]. Front Biosci, 2006, 11 (1):1164-1188.
[12]
YUAN T, QI B, JIANG Z, et al. Dual FLT3 inhibitors: against the drug resistance of acute myeloid leukemia in recent decade [J]. Eur J Med Chem, 2019, 178: 468-483.
[13]
LI C, LIU L, LIANG L, et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia [J]. Mol Cancer Ther, 2015, 14 (2):375-383.
[14]
WANG Y, ZHI Y, JIN Q, et al. Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)- N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK- kinase inhibitor with potentially high efficiency against acute myelocytic leukemia [J]. J Med Chem, 2018, 61 (4):1499-1518.
[15]
LINGER R M, LEE-SHERICK A B, DERYCKERE D, et al. Mer receptor tyrosine kinase is a therapeutic target in pre-B cell acute lymphoblastic leukemia [J]. Blood, 2013, 122 (9):1599-1609.
[16]
LEE-SHERICK A B, ZHANG W, MENACHOF K K, et al. Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia [J]. Oncotarget, 2015, 6 (9):6722-6736.
[17]
HSU Y C, COUMAR M S, WANG W C, et al. Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: rational design, synthesis, in vitro and in vivo evaluation [J]. Oncotarget, 2016, 7 (52):86239-86256.
[18]
SANTOS C D, MCDONALD T, HO Y W, et al. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents [J]. Blood, 2013, 122 (11):1900-1913.
[19]
LAROCQUE E, NAGANNA N, MA X, et al. Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors potently inhibit proliferation of acute myeloid leukemia cell lines [J]. Future Med Chem, 2017, 9 (11):1213-1225.
[20]
BEN-BATALLA I, SCHULTZE A, WROBLEWSKI M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma [J]. Blood, 2013, 122 (14):2443-2452.
[21]
JANNING M, BEN-BATALLA I, LOGES S. Axl inhibition: a potential road to a novel acute myeloid leukemia therapy? [J]. Expert Rev Hematol, 2015, 8 (2):135-138.
[22]
MORI M, KANEKO N, UENO Y, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia [J]. Invest New Drugs, 2017, 35 (5):556-565.
[23]
NAWIJIN M C, ALENDAR A, BERNS A. For better or for worse: the role of Pim oncogenes in tumorigenesis [J]. Nat Rev Cancer, 2011, 11 (1):23-34.
[24]
KIM K T, BAIRD K, AHN J Y, et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival [J]. Blood, 2005, 105 (4):1759-1767.
[25]
GREEN A S, MACIEL T T, HOSPITAL M A, et al. Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia [J]. Sci Adv, 2015, 1 (8):e1500221.
[26]
KAPOOR S, NATARAJAN K, BALDWIN P R, et al. Concurrent inhibition of Pim and FLT3 kinases enhances apoptosis of FLT3-ITD acute myeloid leukemia cells through increased Mcl-1 proteasomal degradation [J]. Clin Cancer Res, 2018, 24 (1):234-247.
[27]
CZARDYBON W, WINDAK R, GOLAS A, et al. A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia [J]. Oncotarget, 2018, 9 (24):16917-16931.
[28]
PUENTE-MNOCADA N, COSTALES P, ANTOLÍN I, et al. Inhibition of FLT3 and PIM kinases by EC-70124 exerts potent activity in preclinical models of acute myeloid leukemia [J]. Mol Cancer Ther, 2018, 17 (3):614-624.
[29]
WANG Y, KRIVTSOV A V, SINHA A U, et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML [J]. Science, 2010, 327 (5973):1650-1653.
[30]
MCCUBREY J A, STEELMAN L S, BERTRAND F E, et al. Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention [J]. Leukemia, 2014, 28 (1):15-33.
[31]
MA S, YANG L L, NIU T, et al. SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML [J]. Sci Rep, 2015, 5: 15646.
[32]
EFREMOV D G, LAURENTI L. The Syk kinase as a therapeutic target in leukemia and lymphoma [J]. Expert Opin Investig Drugs, 2011, 20 (5):623-636.
[33]
WEISBERG E L, PUISSANT A, STONE R, et al. Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase [J]. Oncotarget, 2017, 8 (32):52026-52044.
[34]
LAM B, ARIKAWA Y, CRAMLETT J, et al. Discovery of TAK-659 an orally available investigational inhibitor of spleen tyrosine kinase (SYK) [J]. Bioorg Med Chem Lett, 2016, 26 (24):5947-5950.
[35]
ALACHKAR H, MUTONGA M, MALNASSY G, et al. T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia [J]. Oncotarget, 2015, 6 (32):33410-33425.
[36]
DAYAL N, OPOKU-TEMENG C, HERNANDEZ D E, et al. Dual FLT3/TOPK inhibitor with activity against FLT3-ITD secondary mutations potently inhibits acute myeloid leukemia cell lines [J]. Future Med Chem, 2018, 10 (7):823-835.
[37]
YAMAURA T, NAKATAMI T, UDA K, et al. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations [J]. Blood, 2018, 131 (4):426-438.
[38]
CHANG E, GANGULY S, RAKLHOWA T, et al. The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells [J]. Leukemia, 2016, 30 (5):1025-1032.
[39]
HE Y, SUN L, XU Y, et al. Combined inhibition of PI3Kδ and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia [J]. Cancer Lett, 2018, 420: 49-59.
[40]
GREGORY M A, NEMKOV T, REIZS J A, et al. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia [J]. Exp Hematol, 2018, 58: 52-58.
[41]
ZHANG W, LY C, ISHIZAWA J, et al. Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial [J]. Haematologica, 2018, 103 (10):1642-1653.
[42]
BURSLEM G M, SONG J, CHEN X, et al. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion [J]. J Am Chem Soc, 2018, 140 (48):16428-16432.
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