| Structural highlights
5x02 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | FLT3, CD135, FLK2, STK1 (HUMAN) |
| Activity: | Receptor protein-tyrosine kinase, with EC number 2.7.10.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[FLT3_HUMAN] Defects in FLT3 are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase.[1] [2] [3] [4] [5] [6] [7] [8]
Function
[FLT3_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Publication Abstract from PubMed
An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.
A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations.,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 Blood. 2018 Jan 25;131(4):426-438. doi: 10.1182/blood-2017-05-786657. Epub 2017, Nov 29. PMID:29187377[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000 Dec 1;96(12):3907-14. PMID:11090077
- ↑ Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M, Berdel WE, Serve H. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005 Nov 1;65(21):9643-50. PMID:16266983 doi:10.1158/0008-5472.CAN-05-0422
- ↑ Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, Tsuchida M, Sugita K, Ida K, Hayashi Y. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004 Feb 1;103(3):1085-8. Epub 2003 Sep 22. PMID:14504097 doi:10.1182/blood-2003-02-0418
- ↑ Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998 Sep;12(9):1333-7. PMID:9737679
- ↑ Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL, Lange BJ, Gilliland DG, Radich JP. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood. 2008 May 15;111(10):4930-3. doi: 10.1182/blood-2008-01-117770. Epub 2008, Feb 27. PMID:18305215 doi:10.1182/blood-2008-01-117770
- ↑ Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001 Apr 15;97(8):2434-9. PMID:11290608
- ↑ Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996 Dec;10(12):1911-8. PMID:8946930
- ↑ Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001 Jun;113(4):983-8. PMID:11442493
- ↑ Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM, et al.. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):459-63. PMID:7507245
- ↑ Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukoc Biol. 1999 Mar;65(3):372-80. PMID:10080542
- ↑ Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000 Dec 1;96(12):3907-14. PMID:11090077
- ↑ Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M, Berdel WE, Serve H. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005 Nov 1;65(21):9643-50. PMID:16266983 doi:10.1158/0008-5472.CAN-05-0422
- ↑ Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, Gilliland DG. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006 Aug 15;108(4):1339-45. Epub 2006 Apr 20. PMID:16627759 doi:10.1182/blood-2005-11-011429
- ↑ Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H, Niiro H, Takenaka K, Nagafuji K, Harada M, Ishikawa F, Akashi K. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol. 2008 Jun 1;180(11):7358-67. PMID:18490735
- ↑ Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prebet T, Dubreuil P, De Sepulveda P. FES kinases are required for oncogenic FLT3 signaling. Leukemia. 2010 Apr;24(4):721-8. doi: 10.1038/leu.2009.301. Epub 2010 Jan 28. PMID:20111072 doi:10.1038/leu.2009.301
- ↑ Chen W, Drakos E, Grammatikakis I, Schlette EJ, Li J, Leventaki V, Staikou-Drakopoulou E, Patsouris E, Panayiotidis P, Medeiros LJ, Rassidakis GZ. mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells. Mol Cancer. 2010 Nov 10;9:292. doi: 10.1186/1476-4598-9-292. PMID:21067588 doi:10.1186/1476-4598-9-292
- ↑ Arora D, Stopp S, Bohmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Ronnstrand L, Tanzer S, Bauer R, Bohmer FD, Muller JP. Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. J Biol Chem. 2011 Apr 1;286(13):10918-29. doi: 10.1074/jbc.M110.205021. Epub 2011, Jan 24. PMID:21262971 doi:10.1074/jbc.M110.205021
- ↑ Zheng R, Bailey E, Nguyen B, Yang X, Piloto O, Levis M, Small D. Further activation of FLT3 mutants by FLT3 ligand. Oncogene. 2011 Sep 22;30(38):4004-14. doi: 10.1038/onc.2011.110. Epub 2011 Apr, 25. PMID:21516120 doi:10.1038/onc.2011.110
- ↑ Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R, Tsuchida M, Sugita K, Ida K, Hayashi Y. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004 Feb 1;103(3):1085-8. Epub 2003 Sep 22. PMID:14504097 doi:10.1182/blood-2003-02-0418
- ↑ 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 Jan 25;131(4):426-438. doi: 10.1182/blood-2017-05-786657. Epub 2017, Nov 29. PMID:29187377 doi:http://dx.doi.org/10.1182/blood-2017-05-786657
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