TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tum...

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Veröffentlicht in:	Leukemia Jg. 26; H. 2; S. 236 - 243
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.02.2012 Nature Publishing Group
Schlagworte:	Acute myeloid leukemia Animal models Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis Bioaccumulation Biological and medical sciences Cancer Cancer Research Care and treatment Cell cycle Cell Line, Transformed Cells (biology) Critical Care Medicine Cyclin-dependent kinase Cyclin-dependent kinases Cyclin-Dependent Kinases - antagonists & inhibitors Disease Models, Animal Dosage Dosage and administration Enzyme inhibitors Female fms-Like Tyrosine Kinase 3 - antagonists & inhibitors Hematologic and hematopoietic diseases Hematology Heterocyclic Compounds, 4 or More Rings - pharmacology Heterocyclic Compounds, 4 or More Rings - therapeutic use Humans Intensive Internal Medicine Janus kinase 2 Janus Kinase 2 - antagonists & inhibitors Kinases Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical prognosis Medical sciences Medicine Medicine & Public Health Mice Mice, Inbred BALB C Oncology original-article Patients Pharmacokinetics Polycythemia Polycythemia vera Progenitor cells Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Signaling Stem cells Tumor cell lines Tumors Xenografts Xenotransplantation Singapore United States > US multi-kinase inhibitor AML TG02 CDK JAK2 FLT3 Acute myelogenous leukemia Hematology Enzyme FLT3 gene JAK2 protein tyrosine kinase Transferases Malignant hemopathy trk receptor Cyclin dependent kinase inhibitor Kinase C-Onc gene Protein-tyrosine kinase Protooncogene Cancer
ISSN:	0887-6924, 1476-5551, 1476-5551
Online-Zugang:	Volltext
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Beschreibung
Zusammenfassung:	TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo , TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/leu.2011.218