FLT3

Synonyms

EC 2.7.10, EC:2.7.10.1, Receptor-type tyrosine-protein kinase FLT3, FLT3, FLT-3, FLK2, STK-1, FL cytokine receptor, Fms Related Tyrosine Kinase 3, Stem Cell Tyrosine Kinase 1, CD135 Antigen, CD135, STK1, Growth Factor Receptor Tyrosine Kinase Type III, Fms-Related Tyrosine Kinase 3, Fetal Liver Kinase 2, Fetal Liver Kinase-2, EC 2.7.10.1, fms-Like Tyrosine Kinase 3, Fms Related Receptor Tyrosine Kinase 3, FLK-2

Description

Tyrosine-protein kinase receptor FLT3 is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).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.

KO Status

F2 (-/-)

Drug Information

Launched drugs: 10
Drugs in clinical trials: 30
Latest Research Phase: Approved

Drug Name

Code

Phase

Company

Indications

Clinical Trials

Pexidartinib

PLX-3397

Approved

Daiichi Sankyo Co Ltd

Giant Cell Tumor of Tendon Sheath, Solid tumours, Synovitis, Pigmented Villonodular, Hodgkin Disease, Arthritis, Rheumatoid, Glioblastoma, Giant Cell Tumors, Prostatic Neoplasms, Gastrointestinal Stromal Tumors, Leukemia, Myeloid, Acute

Fedratinib

TG-101348, SAR-302503

Approved

Sanofi

Hematologic Neoplasms, Solid tumours, Polycythemia Vera, Myeloproliferative Disorders, Kidney Diseases, Primary Myelofibrosis, Hepatic Insufficiency, Thrombocythemia, Essential

Quizartinib

AC-220, ASP-2689, AC-010220

Approved

Ambit Biosciences

Solid tumours, Leukemia, Myelodysplastic Syndromes, Myeloproliferative Disorders, Hepatic Insufficiency, Leukemia, Myeloid, Acute

Ponatinib Hydrochloride

AP-24534, INCB-84344, AP24534 HCl, AP24534-HCL, AP24534 hydrochloride

Approved

Ariad

Leukemia, Leukemia, Myeloid, Accelerated Phase, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Solid tumours, Hematologic Neoplasms, Blast Crisis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Chronic-Phase, Philadelphia Chromosome, Gastrointestinal Stromal Tumors, Leukemia, Myeloid, Acute, Lymphoma, Leukemia, Biphenotypic, Acute

Sunitinib Malate

SU-11248, SU-010398, PHA-290940, PNU-290940, PHA-290940AD, PNU-290940AD, SU-011248-L-malate salt, GB-102

Approved

Pfizer Pharmaceuticals Ltd (China)

Kidney Neoplasms, Liver Neoplasms, Solid tumours, Carcinoma, Renal Cell, Carcinoma, Islet Cell, Stomach Neoplasms, Pancreatic neuroendocrine tumors (pNET), Pancreatic Neoplasms, Kidney Diseases, Neuroendocrine Tumors, Urologic Diseases, Prostatic Neoplasms, Diabetic macular oedema, Breast Neoplasms, Gastrointestinal Stromal Tumors, Colorectal Neoplasms, Urologic Neoplasms, Urogenital Neoplasms, Carcinoma, Hepatocellular, Carcinoma, Non-Small-Cell Lung, Macular Degeneration, Retinal Vein Occlusion

Nintedanib Esylate

BIBF-1120

Approved

C.H. Boehringer Sohn Ag & Co. Kg

Ovarian Neoplasms, Solid tumours, Carcinoma, Renal Cell, Scleroderma, Systemic, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Pulmonary Fibrosis, Multiple Myeloma, Prostatic Neoplasms, Peritoneal Neoplasms, Colorectal Neoplasms, Hepatic Insufficiency, Genital Neoplasms, Female, Carcinoma, Hepatocellular, Carcinoma, Non-Small-Cell Lung

Midostaurin

PKC-412, PKC-412A, CGP-41231, CGP-41251

Approved

Novartis Pharma Ag

Hematologic Neoplasms, Leukemia, Mastocytosis, Systemic, Leukemia, Mast-Cell, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hepatic Insufficiency, Leukemia, Myeloid, Acute, Mastocytosis

Gilteritinib Fumarate

ASP-2215 hemifumarate, ASP-2215, 66D-92MGC8M (UNII code)

Approved

Astellas Pharma Inc

Solid tumours, Renal Insufficiency, Hepatic Insufficiency, Leukemia, Myeloid, Acute

Brigatinib

AP-26113

Approved

Takeda Pharmaceutical Co Ltd, Ariad

Solid tumours, Carcinoma, Myofibroma, Lymphoma, Large-Cell, Anaplastic, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung

Sorafenib Tosylate

NSC-724772, BAY-43-0006, BAY-43-9006, BAY-54-9085

Approved

Onyx Pharmaceuticals Inc

Liver Neoplasms, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Ovarian Neoplasms, Solid tumours, Kidney Neoplasms, Carcinoma, Renal Cell, Carcinoma, Pancreatic Neoplasms, Neoplasms, Kidney Diseases, Liver Diseases, Breast Neoplasms, Hepatitis B, Hepatitis C, Thyroid Neoplasms, Lung Neoplasms, Carcinoma, Hepatocellular, Carcinoma, Non-Small-Cell Lung, Melanoma, Fasting, Neoplasm Metastasis

References

Title

Authors

Source

Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex

Verstraete K., Vandriessche G., Januar M., Elegheert J., Shkumatov A.V., Desfosses A., Van Craenenbroeck K., Svergun D.I., Gutsche I., Vergauwen B., Savvides S.N.,

Blood 118:60-68(2011)

Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia

Abu-Duhier F.M., Goodeve A.C., Wilson G.A., Care R.S., Peake I.R., Reilly J.T.,

Br. J. Haematol. 113:983-988(2001)

Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies

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.,

Blood 97:2434-2439(2001)

FES kinases are required for oncogenic FLT3 signaling

Voisset E., Lopez S., Chaix A., Georges C., Hanssens K., Prebet T., Dubreuil P., De Sepulveda P.,

Leukemia 24:721-728(2010)

Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation

Buchwald M., Pietschmann K., Muller J.P., Bohmer F.D., Heinzel T., Kramer O.H.,

Leukemia 24:1412-1421(2010)

mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells

Chen W., Drakos E., Grammatikakis I., Schlette E.J., Li J., Leventaki V., Staikou-Drakopoulou E., Patsouris E., Panayiotidis P., Medeiros L.J., Rassidakis G.Z.,

Mol. Cancer 9:292-292(2010)

Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling

Arora D., Stopp S., Bohmer S.A., Schons J., Godfrey R., Masson K., Razumovskaya E., Ronnstrand L., Tanzer S., Bauer R., Bohmer F.D., Muller J.P.,

J. Biol. Chem. 286:10918-10929(2011)

Further activation of FLT3 mutants by FLT3 ligand

Zheng R., Bailey E., Nguyen B., Yang X., Piloto O., Levis M., Small D.,

Oncogene 30:4004-4014(2011)

The role of FLT3 in haematopoietic malignancies

Stirewalt D.L., Radich J.P.,

Nat. Rev. Cancer 3:650-665(2003)

Structural and functional alterations of FLT3 in acute myeloid leukemia

Meshinchi S., Appelbaum F.R.,

Clin. Cancer Res. 15:4263-4269(2009)

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