Developments of Fms-like Tyrosine Kinase 3 Inhibitors as Anticancer Agents for AML Treatment


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Abstract

Background::FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy.

Methods::In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents.

Results::In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed.

Conclusion::Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

About the authors

Chenchen Ma

College of Integrated Traditional Chinese and Western Medicine, Shandong University of Traditional Chinese Medicine

Email: info@benthamscience.net

Siyuan Cui

Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

Ruirong Xu

Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Chung, H.J.; Kamli, M.R.; Lee, H.J.; Ha, J.D.; Cho, S.Y.; Lee, J.; Kong, J.Y.; Han, S.Y. Discovery of quinolinone derivatives as potent FLT3 inhibitors. Biochem. Biophys. Res. Commun., 2014, 445(3), 561-565. doi: 10.1016/j.bbrc.2014.02.029 PMID: 24530392
  2. Short, N.J.; Rytting, M.E.; Cortes, J.E. Acute myeloid leukaemia. Lancet, 2018, 392(10147), 593-606. doi: 10.1016/S0140-6736(18)31041-9 PMID: 30078459
  3. De Kouchkovsky, I.; Abdul-Hay, M. Acute myeloid leukemia: A comprehensive review and 2016 update. Blood Cancer J., 2016, 6(7), e441. doi: 10.1038/bcj.2016.50 PMID: 27367478
  4. Rowe, J.M. Changing trends in the therapy of acute myeloid leukemia. Best Pract. Res. Clin. Haematol., 2021, 34(4), 101333. doi: 10.1016/j.beha.2021.101333 PMID: 34865705
  5. Molica, M.; Mazzone, C.; Niscola, P.; Carmosino, I.; Di Veroli, A.; De Gregoris, C.; Bonanni, F.; Perrone, S.; Cenfra, N.; Fianchi, L.; Piccioni, A.L.; Spadea, A.; Luzi, G.; Mengarelli, A.; Cudillo, L.; Maurillo, L.; Pagano, L.; Breccia, M.; Rigacci, L.; De Fabritiis, P. Identification of predictive factors for overall survival and response during hypomethylating treatment in very elderly (≥75 Years) acute myeloid leukemia patients: A multicenter real-life experience. Cancers, 2022, 14(19), 4897. doi: 10.3390/cancers14194897 PMID: 36230820
  6. Fedorov, K.; Maiti, A.; Konopleva, M. Targeting FLT3 mutation in acute myeloid leukemia: Current strategies and future directions. Cancers, 2023, 15(8), 2312. doi: 10.3390/cancers15082312 PMID: 37190240
  7. Elgarten, C.W.; Aplenc, R. Pediatric acute myeloid leukemia: Updates on biology, risk stratification, and therapy. Curr. Opin. Pediatr., 2020, 32(1), 57-66. doi: 10.1097/MOP.0000000000000855 PMID: 31815781
  8. Papaemmanuil, E.; Gerstung, M.; Bullinger, L.; Gaidzik, V.I.; Paschka, P.; Roberts, N.D.; Potter, N.E.; Heuser, M.; Thol, F.; Bolli, N.; Gundem, G.; Van Loo, P.; Martincorena, I.; Ganly, P.; Mudie, L.; McLaren, S.; O’Meara, S.; Raine, K.; Jones, D.R.; Teague, J.W.; Butler, A.P.; Greaves, M.F.; Ganser, A.; Döhner, K.; Schlenk, R.F.; Döhner, H.; Campbell, P.J. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med., 2016, 374(23), 2209-2221. doi: 10.1056/NEJMoa1516192 PMID: 27276561
  9. Daver, N.; Schlenk, R.F.; Russell, N.H.; Levis, M.J. Targeting FLT3 mutations in AML: Review of current knowledge and evidence. Leukemia, 2019, 33(2), 299-312. doi: 10.1038/s41375-018-0357-9 PMID: 30651634
  10. Zhong, Y.; Qiu, R.Z.; Sun, S.L.; Zhao, C.; Fan, T.Y.; Chen, M.; Li, N.G.; Shi, Z.H. Small-molecule fms-like tyrosine kinase 3 inhibitors: An attractive and efficient method for the treatment of acute myeloid leukemia. J. Med. Chem., 2020, 63(21), 12403-12428. doi: 10.1021/acs.jmedchem.0c00696 PMID: 32659083
  11. Hassanein, M.; Almahayni, M.H.; Ahmed, S.O.; Gaballa, S.; El Fakih, R. FLT3 inhibitors for treating acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk., 2016, 16(10), 543-549. doi: 10.1016/j.clml.2016.06.002 PMID: 27450971
  12. Tallis, E.; Borthakur, G. Novel treatments for relapsed/refractory acute myeloid leukemia with FLT3 mutations. Expert Rev. Hematol., 2019, 12(8), 621-640. doi: 10.1080/17474086.2019.1635882 PMID: 31232619
  13. Wu, M.; Li, C.; Zhu, X. FLT3 inhibitors in acute myeloid leukemia. J. Hematol. Oncol., 2018, 11(1), 133. doi: 10.1186/s13045-018-0675-4 PMID: 30514344
  14. Wang, Z.; Cai, J.; Cheng, J.; Yang, W.; Zhu, Y.; Li, H.; Lu, T.; Chen, Y.; Lu, S. FLT3 inhibitors in acute myeloid leukemia: Challenges and recent developments in overcoming resistance. J. Med. Chem., 2021, 64(6), 2878-2900. doi: 10.1021/acs.jmedchem.0c01851 PMID: 33719439
  15. Hogan, F.L.; Williams, V.; Knapper, S. FLT3 inhibition in acute myeloid leukaemia – current knowledge and future prospects. Curr. Cancer Drug Targets, 2020, 20(7), 513-531. doi: 10.2174/1570163817666200518075820 PMID: 32418523
  16. Zhai, J.; Li, C.; Sun, B.; Wang, S.; Cui, Y.; Gao, Q.; Sang, F. Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines. Bioorg. Med. Chem. Lett., 2022, 78, 129041. doi: 10.1016/j.bmcl.2022.129041 PMID: 36332882
  17. O’Farrell, A.M.; Abrams, T.J.; Yuen, H.A.; Ngai, T.J.; Louie, S.G.; Yee, K.W.; Wong, L.M.; Hong, W.; Lee, L.B.; Town, A.; Smolich, B.D.; Manning, W.C.; Murray, L.J.; Heinrich, M.C.; Cherrington, J.M. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, 2003, 101(9), 3597-3605. PMID: 12531805
  18. Chow, L.Q.M.; Eckhardt, S.G. Sunitinib: From rational design to clinical efficacy. J. Clin. Oncol., 2007, 25(7), 884-896. doi: 10.1200/JCO.2006.06.3602 PMID: 17327610
  19. Fiedler, W.; Serve, H.; Döhner, H.; Schwittay, M.; Ottmann, O.G.; O’Farrell, A.M.; Bello, C.L.; Allred, R.; Manning, W.C.; Cherrington, J.M.; Louie, S.G.; Hong, W.; Brega, N.M.; Massimini, G.; Scigalla, P.; Berdel, W.E.; Hossfeld, D.K. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood, 2005, 105(3), 986-993. doi: 10.1182/blood-2004-05-1846 PMID: 15459012
  20. Nemes, Z.; Takács-Novák, K.; Völgyi, G.; Valko, K.; Béni, S.; Horváth, Z.; Szokol, B.; Breza, N.; Dobos, J.; Szántai-Kis, C.; Illyés, E.; Boros, S.; Kok, R.J.; Őrfi, L. Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML. Bioorg. Med. Chem. Lett., 2018, 28(14), 2391-2398. doi: 10.1016/j.bmcl.2018.06.026 PMID: 29935772
  21. Bensinger, D.; Stubba, D.; Cremer, A.; Kohl, V.; Waßmer, T.; Stuckert, J.; Engemann, V.; Stegmaier, K.; Schmitz, K.; Schmidt, B. Virtual screening identifies irreversible fms-like tyrosine kinase 3 inhibitors with activity toward resistance-conferring mutations. J. Med. Chem., 2019, 62(5), 2428-2446. doi: 10.1021/acs.jmedchem.8b01714 PMID: 30742435
  22. Ma, F.; Liu, P.; Lei, M.; Liu, J.; Wang, H.; Zhao, S.; Hu, L. Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3). Eur. J. Med. Chem., 2017, 127, 72-86. doi: 10.1016/j.ejmech.2016.12.038 PMID: 28038328
  23. Wang, J.; Pan, X.; Song, Y.; Liu, J.; Ma, F.; Wang, P.; Liu, Y.; Zhao, L.; Kang, D.; Hu, L. Discovery of a potent and selective FLT3 inhibitor ( Z )- N -(5-((5-Fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1 H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propanamide with improved drug-like properties and superior efficacy in flt3-itd-positive acute myeloid leukemia. J. Med. Chem., 2021, 64(8), 4870-4890. doi: 10.1021/acs.jmedchem.0c02247 PMID: 33797247
  24. Marko, D.; Schätzle, S.; Friedel, A.; Genzlinger, A.; Zankl, H.; Meijer, L.; Eisenbrand, G. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br. J. Cancer, 2001, 84(2), 283-289. doi: 10.1054/bjoc.2000.1546 PMID: 11161389
  25. Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A.L.; Myrianthopoulos, V.; Mikros, E.; Tarricone, A.; Musacchio, A.; Roe, S.M.; Pearl, L.; Leost, M.; Greengard, P.; Meijer, L. Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J. Med. Chem., 2004, 47(4), 935-946. doi: 10.1021/jm031016d PMID: 14761195
  26. Choi, S.J.; Moon, M.J.; Lee, S.D.; Choi, S.U.; Han, S.Y.; Kim, Y.C. Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells. Bioorg. Med. Chem. Lett., 2010, 20(6), 2033-2037. doi: 10.1016/j.bmcl.2010.01.039 PMID: 20153646
  27. Han, H.L.J.L.P.J.J.C.S-Y. Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia. Oncotarget, 2018, 9(1), 924-936.
  28. Jeong, P.; Moon, Y.; Lee, J.H.; Lee, S.D.; Park, J.; Lee, J.; Kim, J.; Lee, H.J.; Kim, N.Y.; Choi, J.; Heo, J.D.; Shin, J.E.; Park, H.W.; Kim, Y.G.; Han, S.Y.; Kim, Y.C. Discovery of orally active indirubin-3′-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia. Eur. J. Med. Chem., 2020, 195, 112205. doi: 10.1016/j.ejmech.2020.112205 PMID: 32272419
  29. Kleinmaier, R.; Keller, M.; Igel, P.; Buschauer, A.; Gschwind, R.M. Conformations, conformational preferences, and conformational exchange of N′-substituted N-acylguanidines: Intermolecular interactions hold the key. J. Am. Chem. Soc., 2010, 132(32), 11223-11233. doi: 10.1021/ja103756y PMID: 20698689
  30. Solinas, A.; Faure, H.; Roudaut, H.; Traiffort, E.; Schoenfelder, A.; Mann, A.; Manetti, F.; Taddei, M.; Ruat, M. Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity. J. Med. Chem., 2012, 55(4), 1559-1571. doi: 10.1021/jm2013369 PMID: 22268551
  31. Jagtap, A.D.; Chang, P.T.; Liu, J.R.; Wang, H.C.; Kondekar, N.B.; Shen, L.J.; Tseng, H.W.; Chen, G.S.; Chern, J.W. Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia. Eur. J. Med. Chem., 2014, 85, 268-288. doi: 10.1016/j.ejmech.2014.07.108 PMID: 25089810
  32. El-Hussieny, M.; El-Sayed, N.F.; Fouad, M.A.; Ewies, E.F. Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia. Bioorg. Chem., 2021, 117, 105421. doi: 10.1016/j.bioorg.2021.105421 PMID: 34666258
  33. Shirvani, P.; Fayyazi, N.; Van Belle, S.; Debyser, Z.; Christ, F.; Saghaie, L.; Fassihi, A. Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment. Bioorg. Med. Chem. Lett., 2022, 70, 128784. doi: 10.1016/j.bmcl.2022.128784 PMID: 35569690
  34. Zhao, J.C.; Agarwal, S.; Ahmad, H.; Amin, K.; Bewersdorf, J.P.; Zeidan, A.M. A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev., 2022, 52, 100905. doi: 10.1016/j.blre.2021.100905 PMID: 34774343
  35. 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. Ther. Adv. Hematol., 2017, 8(9), 245-261. doi: 10.1177/2040620717721459 PMID: 29051803
  36. Levis, M. Midostaurin approved for FLT3-mutated AML. Blood, 2017, 129(26), 3403-3406. doi: 10.1182/blood-2017-05-782292 PMID: 28546144
  37. Stone, R.M.; DeAngelo, D.J.; Klimek, V.; Galinsky, I.; Estey, E.; Nimer, S.D.; Grandin, W.; Lebwohl, D.; Wang, Y.; Cohen, P.; Fox, E.A.; Neuberg, D.; Clark, J.; Gilliland, D.G.; Griffin, J.D. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small- molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood, 2005, 105(1), 54-60. doi: 10.1182/blood-2004-03-0891 PMID: 15345597
  38. Fischer, T.; Stone, R.M.; DeAngelo, D.J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E.J.; Schiller, G.J.; Klimek, V.M.; Nimer, S.D.; Gilliland, D.G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F.J. Phase IIB trial of oral Midostaurin (PKC412), the FMS- like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild- type or mutated FLT3. J. Clin. Oncol., 2010, 28(28), 4339-4345. doi: 10.1200/JCO.2010.28.9678 PMID: 20733134
  39. Shabbir, M.; Stuart, R. Lestaurtinib, a multitargeted tyrosinse kinase inhibitor: From bench to bedside. Expert Opin. Investig. Drugs, 2010, 19(3), 427-436. doi: 10.1517/13543781003598862 PMID: 20141349
  40. Levis, M.; Allebach, J.; Tse, K-F.; Zheng, R.; Baldwin, B.R.; Smith, B.D.; Jones-Bolin, S.; Ruggeri, B.; Dionne, C.; Small, D. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood, 2002, 99(11), 3885-3891. doi: 10.1182/blood.V99.11.3885
  41. Levis, M.; Ravandi, F.; Wang, E.S.; Baer, M.R.; Perl, A.; Coutre, S.; Erba, H.; Stuart, R.K.; Baccarani, M.; Cripe, L.D.; Tallman, M.S.; Meloni, G.; Godley, L.A.; Langston, A.A.; Amadori, S.; Lewis, I.D.; Nagler, A.; Stone, R.; Yee, K.; Advani, A.; Douer, D.; Wiktor-Jedrzejczak, W.; Juliusson, G.; Litzow, M.R.; Petersdorf, S.; Sanz, M.; Kantarjian, H.M.; Sato, T.; Tremmel, L.; Bensen-Kennedy, D.M.; Small, D.; Smith, B.D. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood, 2011, 117(12), 3294-3301. doi: 10.1182/blood-2010-08-301796 PMID: 21270442
  42. Gebru, M.T.; Atkinson, J.M.; Young, M.M.; Zhang, L.; Tang, Z.; Liu, Z.; Lu, P.; Dower, C.M.; Chen, L.; Annageldiyev, C.; Sharma, A.; Imamura Kawasawa, Y.; Zhao, Z.; Miller, B.A.; Claxton, D.F.; Wang, H.G. Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia. Blood, 2020, 136(9), 1067-1079. doi: 10.1182/blood.2019003124 PMID: 32396937
  43. Ma, H.; Nguyen, B.; Li, L.; Greenblatt, S.; Williams, A.; Zhao, M.; Levis, M.; Rudek, M.; Duffield, A.; Small, D. TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo. Blood, 2014, 123(10), 1525-1534. doi: 10.1182/blood-2013-08-523035 PMID: 24408321
  44. Ma, H.S.; Nguyen, B.; Duffield, A.S.; Li, L.; Galanis, A.; Williams, A.B.; Brown, P.A.; Levis, M.J.; Leahy, D.J.; Small, D. FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Cancer Res., 2014, 74(18), 5206-5217. doi: 10.1158/0008-5472.CAN-14-1028 PMID: 25060518
  45. Lopez-Millan, B.; Costales, P.; Gutiérrez-Agüera, F.; Díaz de la Guardia, R.; Roca-Ho, H.; Vinyoles, M.; Rubio-Gayarre, A.; Safi, R.; Castaño, J.; Romecín, P.A.; Ramírez-Orellana, M.; Anguita, E.; Jeremias, I.; Zamora, L.; Rodríguez-Manzaneque, J.C.; Bueno, C.; Morís, F.; Menendez, P. The multi-kinase inhibitor EC-70124 is a promising candidate for the treatment of flt3-itd-positive acute myeloid leukemia. Cancers, 2022, 14(6), 1593. doi: 10.3390/cancers14061593 PMID: 35326743
  46. Puente-Moncada, N.; Costales, P.; Antolín, I.; Núñez, L.E.; Oro, P.; Hermosilla, M.A.; Pérez-Escuredo, J.; Ríos-Lombardía, N.; Sanchez-Sanchez, A.M.; Luño, E.; Rodríguez, C.; Martín, V.; Morís, F. Inhibition of FLT3 and PIM kinases by EC-70124 exerts potent activity in preclinical models of acute myeloid leukemia. Mol. Cancer Ther., 2018, 17(3), 614-624. doi: 10.1158/1535-7163.MCT-17-0530 PMID: 29339551
  47. Grandage, V.L.; Everington, T.; Linch, D.C.; Khwaja, A. Gö6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells. Br. J. Haematol., 2006, 135(3), 303-316. doi: 10.1111/j.1365-2141.2006.06291.x PMID: 16956345
  48. Yoshida, A.; Ookura, M.; Zokumasu, K.; Ueda, T. Gö6976, a FLT3 kinase inhibitor, exerts potent cytotoxic activity against acute leukemia via inhibition of survivin and MCL-1. Biochem. Pharmacol., 2014, 90(1), 16-24. doi: 10.1016/j.bcp.2014.04.002 PMID: 24735609
  49. Keri, R.S.; Hiremathad, A.; Budagumpi, S.; Nagaraja, B.M. Comprehensive review in current developments of benzimidazole-based medicinal chemistry. Chem. Biol. Drug Des., 2015, 86(1), 19-65. doi: 10.1111/cbdd.12462 PMID: 25352112
  50. Vasava, M.S.; Bhoi, M.N.; Rathwa, S.K.; Jethava, D.J.; Acharya, P.T.; Patel, D.B.; Patel, H.D. Benzimidazole: A milestone in the field of medicinal chemistry. Mini Rev. Med. Chem., 2020, 20(7), 532-565. doi: 10.2174/1389557519666191122125453 PMID: 31755386
  51. Ali, A.M.; Tawfik, S.S.; Mostafa, A.S.; Massoud, M.A.M. Benzimidazole-based protein kinase inhibitors: Current perspectives in targeted cancer therapy. Chem. Biol. Drug Des., 2022, 100(5), 656-673. doi: 10.1111/cbdd.14130 PMID: 35962624
  52. Kampa-Schittenhelm, K.M.; Frey, J.; Haeusser, L.A.; Illing, B.; Pavlovsky, A.A.; Blumenstock, G.; Schittenhelm, M.M. Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia. Oncotarget, 2017, 8(47), 82897-82909. doi: 10.18632/oncotarget.19970
  53. Galanis, A.; Ma, H.; Rajkhowa, T.; Ramachandran, A.; Small, D.; Cortes, J.; Levis, M. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood, 2014, 123(1), 94-100. doi: 10.1182/blood-2013-10-529313 PMID: 24227820
  54. Zimmerman, E.I.; Turner, D.C.; Buaboonnam, J.; Hu, S.; Orwick, S.; Roberts, M.S.; Janke, L.J.; Ramachandran, A.; Stewart, C.F.; Inaba, H.; Baker, S.D. Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia. Blood, 2013, 122(22), 3607-3615. doi: 10.1182/blood-2013-07-513044 PMID: 24046014
  55. Friedman, R. The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors. Biochim. Biophys. Acta Rev. Cancer, 2022, 1877(1), 188666. doi: 10.1016/j.bbcan.2021.188666 PMID: 34896257
  56. Garcia, J.S.; Stone, R.M. The development of FLT3 inhibitors in acute myeloid leukemia. Hematol. Oncol. Clin. North Am., 2017, 31(4), 663-680. doi: 10.1016/j.hoc.2017.03.002 PMID: 28673394
  57. Kimura, S. AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer. Curr. Opin. Investig. Drugs, 2010, 11(12), 1442-1449. PMID: 21154126
  58. Steven Howard, V.B.; John, A. Fragment-based discovery of the pyrazol-4-yl urea (at9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J. Med. Chem., 2009, 52, 379-388.
  59. Podesta, J.E.; Sugar, R.; Squires, M.; Linardopoulos, S.; Pearson, A.D.J.; Moore, A.S. Adaptation of the plasma inhibitory activity assay to detect Aurora, ABL and FLT3 kinase inhibition by AT9283 in pediatric leukemia. Leuk. Res., 2011, 35(9), 1273-1275. doi: 10.1016/j.leukres.2011.05.022 PMID: 21665275
  60. Ravandi, F.; Foran, J.; Verstovsek, S.; Cortes, J.; Wierda, W.; Boone, P.; Borthakur, G.; Sweeney, T.; Kantarjian, H. A phase I trial of AT9283, a multitargeted kinase inhibitor, in patients with refractory hematological malignancies. Blood, 2007, 110(11), 904-904. doi: 10.1182/blood.V110.11.904.904
  61. Czardybon, W.; Windak, R.; Gołas, A.; Gałęzowski, M.; Sabiniarz, A.; Dolata, I.; Salwińska, M.; Guzik, P.; Zawadzka, M.; Gabor-Worwa, E.; Winnik, B.; Żurawska, M.; Kolasińska, E.; Wincza, E.; Bugaj, M.; Danielewicz, M.; Majewska, E.; Mazan, M.; Dubin, G.; Noyszewska-Kania, M.; Jabłońska, E.; Szydłowski, M.; Sewastianik, T.; Puła, B.; Szumera-Ciećkiewicz, A.; Prochorec-Sobieszek, M.; Mądro, E.; Lech-Marańda, E.; Warzocha, K.; Tamburini, J.; Juszczyński, P.; Brzózka, K. A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia. Oncotarget, 2018, 9(24), 16917-16931. doi: 10.18632/oncotarget.24747 PMID: 29682194
  62. Dokla, E.M.E.; Abdel-Aziz, A.K.; Milik, S.N.; McPhillie, M.J.; Minucci, S.; Abouzid, K.A.M. Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia. Bioorg. Med. Chem., 2022, 56, 116596. doi: 10.1016/j.bmc.2021.116596 PMID: 35033885
  63. Tian, T.; Zhang, S.; Luo, B.; Yin, F.; Lu, W.; Li, Y.; Huang, K.; Liu, Q.; Huang, P.; Garcia-Manero, G.; Wen, S.; Hu, Y. Identification of the benzoimidazole compound as a selective FLT3 inhibitor by cell-based high-throughput screening of a diversity library. J. Med. Chem., 2022, 65(4), 3597-3605. doi: 10.1021/acs.jmedchem.1c02079 PMID: 35148084
  64. Yen, S.C.; Chen, L.C.; Huang, H.L.; HuangFu, W.C.; Chen, Y.Y.; Eight Lin, T.; Lien, S.T.; Tseng, H.J.; Sung, T.Y.; Hsieh, J.H.; Huang, W.J.; Pan, S.L.; Hsu, K.C. Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach. Bioorg. Chem., 2022, 121, 105675. doi: 10.1016/j.bioorg.2022.105675 PMID: 35182882
  65. Goh, K.C.; Novotny-Diermayr, V.; Hart, S.; Ong, L.C.; Loh, Y.K.; Cheong, A.; Tan, Y.C.; Hu, C.; Jayaraman, R.; William, A.D.; Sun, E.T.; Dymock, B.W.; Ong, K.H.; Ethirajulu, K.; Burrows, F.; Wood, J.M. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia, 2012, 26(2), 236-243. doi: 10.1038/leu.2011.218 PMID: 21860433
  66. Lu, Y.; Ran, T.; Lin, G.; Jin, Q.; Jin, J.; Li, H.; Guo, H.; Lu, T.; Wang, Y. Novel 1H-pyrazole-3-carboxamide derivatives: Synthesis, anticancer evaluation and identification of their DNA-binding interaction. Chem. Pharm. Bull., 2014, 62(3), 238-246. doi: 10.1248/cpb.c13-00676 PMID: 24365978
  67. Wang, Y.; Zhi, Y.; Jin, Q.; Lu, S.; Lin, G.; Yuan, H.; Yang, T.; Wang, Z.; Yao, C.; Ling, J.; Guo, H.; Li, T.; Jin, J.; Li, B.; Zhang, L.; Chen, Y.; Lu, T. Discovery of 4-((7 H-pyrrolo2,3-dpyrimidin-4-yl)amino)-N-(4-((4-methylpi perazin-1-yl)methyl)phenyl)-1 H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-kinase inhibitor with potentially high efficiency against acute myelocytic leukemia. J. Med. Chem., 2018, 61(4), 1499-1518. doi: 10.1021/acs.jmedchem.7b01261 PMID: 29357250
  68. Zhi, Y.; Li, B.; Yao, C.; Li, H.; Chen, P.; Bao, J.; Qin, T.; Wang, Y.; Lu, T.; Lu, S. Discovery of the selective and efficacious inhibitors of FLT3 mutations. Eur. J. Med. Chem., 2018, 155, 303-315. doi: 10.1016/j.ejmech.2018.06.010 PMID: 29894944
  69. Zhi, Y.; Wang, Z.; Yao, C.; Li, B.; Heng, H.; Cai, J.; Xiang, L.; Wang, Y.; Lu, T.; Lu, S. Design and synthesis of 4-(heterocyclic Substituted Amino)-1H-Pyrazole-3-carboxamide derivatives and their potent activity against acute myeloid leukemia (AML). Int. J. Mol. Sci., 2019, 20(22), 5739. doi: 10.3390/ijms20225739 PMID: 31731727
  70. Lin, W.H.; Hsu, J.T.A.; Hsieh, S.Y.; Chen, C.T.; Song, J.S.; Yen, S.C.; Hsu, T.; Lu, C.T.; Chen, C.H.; Chou, L.H.; Yang, Y.N.; Chiu, C.H.; Chen, C.P.; Tseng, Y.J.; Yen, K.J.; Yeh, C.F.; Chao, Y.S.; Yeh, T.K.; Jiaang, W.T. Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3). Bioorg. Med. Chem., 2013, 21(11), 2856-2867. doi: 10.1016/j.bmc.2013.03.083 PMID: 23618709
  71. Heng, H.; Zhi, Y.; Yuan, H.; Wang, Z.; Li, H.; Wang, S.; Tian, J.; Liu, H.; Chen, Y.; Lu, T.; Ran, T.; Lu, S. Discovery of a highly selective FLT3 inhibitor with specific proliferation inhibition against AML cells harboring FLT3-ITD mutation. Eur. J. Med. Chem., 2019, 163, 195-206. doi: 10.1016/j.ejmech.2018.11.063 PMID: 30508668
  72. Heng, H.; Wang, Z.; Li, H.; Huang, Y.; Lan, Q.; Guo, X.; Zhang, L.; Zhi, Y.; Cai, J.; Qin, T.; Xiang, L.; Wang, S.; Chen, Y.; Lu, T.; Lu, S. Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model. Eur. J. Med. Chem., 2019, 176, 248-267. doi: 10.1016/j.ejmech.2019.05.021 PMID: 31103903
  73. Wang, Z.; Cai, J.; Ren, J.; Chen, Y.; Wu, Y.; Cheng, J.; Jia, K.; Huang, F.; Cheng, Z.; Sheng, T.; Song, S.; Heng, H.; Zhu, Y.; Tang, W.; Li, H.; Lu, T.; Chen, Y.; Lu, S. Discovery of a potent FLT3 inhibitor (LT-850-166) with the capacity of overcoming a variety of FLT3 mutations. J. Med. Chem., 2021, 64(19), 14664-14701. doi: 10.1021/acs.jmedchem.1c01196 PMID: 34550682
  74. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L.E.; Bollag, G.; Trail, P.A. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res., 2004, 64(19), 7099-7109. doi: 10.1158/0008-5472.CAN-04-1443 PMID: 15466206
  75. Liu, T.; Ivaturi, V.; Sabato, P.; Gobburu, J.V.S.; Greer, J.M.; Wright, J.J.; Smith, B.D.; Pratz, K.W.; Rudek, M.A. Sorafenib dose recommendation in acute myeloid leukemia based on exposure-flt3 relationship. Clin. Transl. Sci., 2018, 11(4), 435-443. doi: 10.1111/cts.12555 PMID: 29702736
  76. Zhang, W.; Konopleva, M.; Shi, Y.; McQueen, T.; Harris, D.; Ling, X.; Estrov, Z.; Quintás-Cardama, A.; Small, D.; Cortes, J.; Andreeff, M. Mutant FLT3: A direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst., 2008, 100(3), 184-198. doi: 10.1093/jnci/djm328 PMID: 18230792
  77. Ravandi, F.; Cortes, J.E.; Jones, D.; Faderl, S.; Garcia- Manero, G.; Konopleva, M.Y.; O’Brien, S.; Estrov, Z.; Borthakur, G.; Thomas, D.; Pierce, S.R.; Brandt, M.; Byrd, A.; Bekele, B.N.; Pratz, K.; Luthra, R.; Levis, M.; Andreeff, M.; Kantarjian, H.M. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J. Clin. Oncol., 2010, 28(11), 1856-1862. doi: 10.1200/JCO.2009.25.4888 PMID: 20212254
  78. Morin, S.; Giannotti, F.; Mamez, A.C.; Pradier, A.; Masouridi-Levrat, S.; Simonetta, F.; Chalandon, Y. Real- world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption. Front. Oncol., 2023, 13, 1095870. doi: 10.3389/fonc.2023.1095870 PMID: 37007116
  79. Garciaz, S.; Hospital, M.A. FMS-like tyrosine kinase 3 inhibitors in the treatment of acute myeloid leukemia: An update on the emerging evidence and safety profile. OncoTargets Ther., 2023, 16, 31-45. doi: 10.2147/OTT.S236740 PMID: 36698434
  80. Yang, L.L.; Li, G.B.; Ma, S.; Zou, C.; Zhou, S.; Sun, Q.Z.; Cheng, C.; Chen, X.; Wang, L.J.; Feng, S.; Li, L.L.; Yang, S.Y. Structure-activity relationship studies of pyrazolo3,4-dpyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J. Med. Chem., 2013, 56(4), 1641-1655. doi: 10.1021/jm301537p PMID: 23362959
  81. Liang, X.; Wang, B.; Chen, C.; Wang, A.; Hu, C.; Zou, F.; Yu, K.; Liu, Q.; Li, F.; Hu, Z.; Lu, T.; Wang, J.; Wang, L.; Weisberg, E.L.; Li, L.; Xia, R.; Wang, W.; Ren, T.; Ge, J.; Liu, J.; Liu, Q. Discovery of N-(4-(6-acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)aceta mide (CHMFL-FLT3-335) as a potent FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutant selective inhibitor for acute myeloid leukemia. J. Med. Chem., 2019, 62(2), 875-892. doi: 10.1021/acs.jmedchem.8b01594 PMID: 30565931
  82. Cortes, J.E.; Kantarjian, H.; Foran, J.M.; Ghirdaladze, D.; Zodelava, M.; Borthakur, G.; Gammon, G.; Trone, D.; Armstrong, R.C.; James, J.; Levis, M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS- like tyrosine kinase 3-internal tandem duplication status. J. Clin. Oncol., 2013, 31(29), 3681-3687. doi: 10.1200/JCO.2013.48.8783 PMID: 24002496
  83. Tomoya, A.N.T. quizartinib a selective flt3 inhibitor maintains antileukemic activity in preclinical models of ras-mediated midostaurinresistant acute myeloid leukemia cells. Oncotarget, 2020, 11, 943-955. doi: 10.18632/oncotarget.27489
  84. Paul, S.; DiPippo, A.J.; Ravandi, F.; Kadia, T.M. Quizartinib in the treatment of FLT3-internal-tandem duplication- positive acute myeloid leukemia. Future Oncol., 2019, 15(34), 3885-3894. doi: 10.2217/fon-2019-0353 PMID: 31559849
  85. Chen, C.T.; Hsu, J.T.A.; Lin, W.H.; Lu, C.T.; Yen, S.C.; Hsu, T.; Huang, Y.L.; Song, J.S.; Chen, C.H.; Chou, L.H.; Yen, K.J.; Chen, C.P.; Kuo, P.C.; Huang, C.L.; Liu, H.E.; Chao, Y.S.; Yeh, T.K.; Jiaang, W.T. Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations. Eur. J. Med. Chem., 2015, 100, 151-161. doi: 10.1016/j.ejmech.2015.05.008 PMID: 26081023
  86. Xu, Y.; Wang, N.Y.; Song, X.J.; Lei, Q.; Ye, T.H.; You, X.Y.; Zuo, W.Q.; Xia, Y.; Zhang, L.D.; Yu, L.T. Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N′-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo. Bioorg. Med. Chem., 2015, 23(15), 4333-4343. doi: 10.1016/j.bmc.2015.06.033 PMID: 26142317
  87. Wang, A.; Li, X.; Chen, C.; Wu, H.; Qi, Z.; Hu, C.; Yu, K.; Wu, J.; Liu, J.; Liu, X.; Hu, Z.; Wang, W.; Wang, W.; Wang, W.; Wang, L.; Wang, B.; Liu, Q.; Li, L.; Ge, J.; Ren, T.; Zhang, S.; Xia, R.; Liu, J.; Liu, Q. Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1 H -pyrazolo3,4- d pyrimidin-1-yl)phenyl)-3-(5-( tert -butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a highly potent type II FLT3 kinase inhibitor capable of overcoming a variety of FLT3 kinase mutants in FLT3-ITD positive AML. J. Med. Chem., 2017, 60(20), 8407-8424. doi: 10.1021/acs.jmedchem.7b00840 PMID: 28956923
  88. Yuan, X.; Chen, Y.; Zhang, W.; He, J.; Lei, L.; Tang, M.; Liu, J.; Li, M.; Dou, C.; Yang, T.; Yang, L.; Yang, S.; Wei, Y.; Peng, A.; Niu, T.; Xiang, M.; Ye, H.; Chen, L. Identification of pyrrolo2,3-dpyrimidine-based derivatives as potent and orally effective fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia. J. Med. Chem., 2019, 62(8), 4158-4173. doi: 10.1021/acs.jmedchem.9b00223 PMID: 30939008
  89. Cilibrasi, V.; Spanò, V.; Bortolozzi, R.; Barreca, M.; Raimondi, M.V.; Rocca, R.; Maruca, A.; Montalbano, A.; Alcaro, S.; Ronca, R.; Viola, G.; Barraja, P. Synthesis of 2H-Imidazo2′,1′:2,3 1,3thiazolo4,5-eisoindol-8-yl-phenylureas with promising therapeutic features for the treatment of acute myeloid leukemia (AML) with FLT3/ITD mutations. Eur. J. Med. Chem., 2022, 235, 114292. doi: 10.1016/j.ejmech.2022.114292 PMID: 35339838
  90. Ma, S.; Yang, L.L.; Niu, T.; Cheng, C.; Zhong, L.; Zheng, M.W.; Xiong, Y.; Li, L.L.; Xiang, R.; Chen, L.J.; Zhou, Q.; Wei, Y.Q.; Yang, S.Y. SKLB-677, an FLT3 and Wnt/β-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML. Sci. Rep., 2015, 5(1), 15646. doi: 10.1038/srep15646 PMID: 26497577
  91. Zhang, G.; Zhang, W.; Shen, C.; Nan, J.; Chen, M.; Lai, S.; Zhong, J.; Li, B.; Wang, T.; Wang, Y.; Yang, S.; Li, L. Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations. Bioorg. Med. Chem. Lett., 2020, 30(22), 127532. doi: 10.1016/j.bmcl.2020.127532 PMID: 32891702
  92. Sellmer, A.; Pilsl, B.; Beyer, M.; Pongratz, H.; Wirth, L.; Elz, S.; Dove, S.; Henninger, S.J.; Spiekermann, K.; Polzer, H.; Klaeger, S.; Kuster, B.; Böhmer, F.D.; Fiebig, H.H.; Krämer, O.H.; Mahboobi, S. A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia. Eur. J. Med. Chem., 2020, 193, 112232. doi: 10.1016/j.ejmech.2020.112232 PMID: 32199135
  93. Zhang, Q.; Zhao, K.; Zhang, L.; Jiao, X.; Zhang, Y.; Tang, C. Synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(23), 127525. doi: 10.1016/j.bmcl.2020.127525 PMID: 32898697
  94. Qi, B.; Xu, X.; Yang, Y.; Zhou, Y.; Chen, T.; Gong, G.; Yue, X.; Xu, X.; Hu, L.; He, H. Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2. Bioorg. Med. Chem., 2019, 27(10), 2127-2139. doi: 10.1016/j.bmc.2019.03.049 PMID: 30940564
  95. Xu, X.; Hu, L.; Fan, M.; Hu, Z.; Li, Q.; He, H.; Qi, B. Identification of 1,3-thiazinan-4-one urea-based derivatives as potent FLT3/VEGFR2 dual inhibitors for the treatment of acute myeloid leukemia. J. Mol. Struct., 2022, 1250, 131862. doi: 10.1016/j.molstruc.2021.131862
  96. Molica, M.; Perrone, S.; Rossi, M. Gilteritinib: The story of a proceeding success into hard-to-treat FLT3-mutated AML patients. J. Clin. Med., 2023, 12(11), 3647. doi: 10.3390/jcm12113647 PMID: 37297842
  97. Mori, M.; Kaneko, N.; Ueno, Y.; Yamada, M.; Tanaka, R.; Saito, R.; Shimada, I.; Mori, K.; Kuromitsu, S. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest. New Drugs, 2017, 35(5), 556-565. doi: 10.1007/s10637-017-0470-z PMID: 28516360
  98. Kang, C.; Blair, H.A. Gilteritinib: A review in relapsed or refractory FLT3-mutated acute myeloid leukaemia. Target. Oncol., 2020, 15(5), 681-689. doi: 10.1007/s11523-020-00749-3 PMID: 32940858
  99. Usuki, K.; Sakura, T.; Kobayashi, Y.; Miyamoto, T.; Iida, H.; Morita, S.; Bahceci, E.; Kaneko, M.; Kusano, M.; Yamada, S.; Takeshita, S.; Miyawaki, S.; Naoe, T. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study. Cancer Sci., 2018, 109(10), 3235-3244. doi: 10.1111/cas.13749 PMID: 30039554
  100. Jarusiewicz, J.A.; Jeon, J.Y.; Connelly, M.C.; Chen, Y.; Yang, L.; Baker, S.D.; Guy, R.K. Discovery of a diaminopyrimidine FLT3 inhibitor active against acute myeloid leukemia. ACS Omega, 2017, 2(5), 1985-2009. doi: 10.1021/acsomega.7b00144 PMID: 28580438
  101. Yamaura, T.; Nakatani, T.; Uda, K.; Ogura, H.; Shin, W.; Kurokawa, N.; Saito, K.; Fujikawa, N.; Date, T.; Takasaki, M.; Terada, D.; Hirai, A.; Akashi, A.; Chen, F.; Adachi, Y.; Ishikawa, Y.; Hayakawa, F.; Hagiwara, S.; Naoe, T.; Kiyoi, H. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood, 2018, 131(4), 426-438. doi: 10.1182/blood-2017-05-786657 PMID: 29187377
  102. Ferng, T.T.; Terada, D.; Ando, M.; Tarver, T.C.; Chaudhary, F.; Lin, K.C.; Logan, A.C.; Smith, C.C. The irreversible FLT3 inhibitor FF-10101 is active against a diversity of FLT3 inhibitor resistance mechanisms. Mol. Cancer Ther., 2022, 21(5), 844-854. doi: 10.1158/1535-7163.MCT-21-0317 PMID: 35395091
  103. Hart, S.; Goh, K.C.; Novotny-Diermayr, V.; Tan, Y.C.; Madan, B.; Amalini, C.; Ong, L.C.; Kheng, B.; Cheong, A.; Zhou, J.; Chng, W.J.; Wood, J.M. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. Blood Cancer J., 2011, 1(11), e44. doi: 10.1038/bcj.2011.43 PMID: 22829080
  104. Verstovsek, S.; Odenike, O.; Singer, J.W.; Granston, T.; Al-Fayoumi, S.; Deeg, H.J. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J. Hematol. Oncol., 2016, 9(1), 137. doi: 10.1186/s13045-016-0367-x PMID: 27931243
  105. Yang, T.; Hu, M.; Qi, W.; Yang, Z.; Tang, M.; He, J.; Chen, Y.; Bai, P.; Yuan, X.; Zhang, C.; Liu, K.; Lu, Y.; Xiang, M.; Chen, L. Discovery of potent and orally effective dual janus kinase 2/FLT3 inhibitors for the treatment of acute myelogenous leukemia and myeloproliferative neoplasms. J. Med. Chem., 2019, 62(22), 10305-10320. doi: 10.1021/acs.jmedchem.9b01348 PMID: 31670517
  106. Li, X.; Yang, T.; Hu, M.; Yang, Y.; Tang, M.; Deng, D.; Liu, K.; Fu, S.; Tan, Y.; Wang, H.; Chen, Y.; Zhang, C.; Guo, Y.; Peng, B.; Si, W.; Yang, Z.; Chen, L. Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo4,3-bpyridine derivatives as novel dual FLT3/CDK4 inhibitors. Bioorg. Chem., 2022, 121, 105669. doi: 10.1016/j.bioorg.2022.105669 PMID: 35180490
  107. Long, Y.; Yu, M.; Ochnik, A.M.; Karanjia, J.D.; Basnet, S.K.C.; Kebede, A.A.; Kou, L.; Wang, S. Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations. Eur. J. Med. Chem., 2021, 213, 113215. doi: 10.1016/j.ejmech.2021.113215 PMID: 33516985
  108. Al-Shakliah, N.S.; Attwa, M.W.; AlRabiah, H.; Kadi, A.A. Identification and characterization of in vitro, in vivo, and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry. Anal. Methods, 2021, 13(3), 399-410. doi: 10.1039/D0AY02106G PMID: 33410830
  109. Li, Y.; Ye, T.; Xu, L.; Dong, Y.; Luo, Y.; Wang, C.; Han, Y.; Chen, K.; Qin, M.; Liu, Y.; Zhao, Y. Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3. Eur. J. Med. Chem., 2019, 181, 111590. doi: 10.1016/j.ejmech.2019.111590 PMID: 31408808
  110. Tong, L.; Wang, P.; Li, X.; Dong, X.; Hu, X.; Wang, C.; Liu, T.; Li, J.; Zhou, Y. Identification of 2-aminopyrimidine derivatives as FLT3 kinase inhibitors with high selectivity over c-KIT. J. Med. Chem., 2022, 65(4), 3229-3248. doi: 10.1021/acs.jmedchem.1c01792 PMID: 35138851
  111. Cho, H.; Shin, I.; Yoon, H.; Jeon, E.; Lee, J.; Kim, Y.; Ryu, S.; Song, C.; Kwon, N.H.; Moon, Y.; Kim, S.; Kim, N.D.; Choi, H.G.; Sim, T. Identification of thieno3,2-dpyrimidine derivatives as dual inhibitors of focal adhesion kinase and fms-like tyrosine kinase 3. J. Med. Chem., 2021, 64(16), 11934-11957. doi: 10.1021/acs.jmedchem.1c00459 PMID: 34324343

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