title: TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties.
abstract: 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.
authors.affiliation: SBIO Pte Ltd, Singapore, Republic of Singapore. keechuan_goh@sbio.com
authors.forename: K C
authors.initials: KC
authors.lastname: Goh
authors.forename: V
authors.initials: V
authors.lastname: Novotny-Diermayr
authors.forename: S
authors.initials: S
authors.lastname: Hart
authors.forename: L C
authors.initials: LC
authors.lastname: Ong
authors.forename: Y K
authors.initials: YK
authors.lastname: Loh
authors.forename: A
authors.initials: A
authors.lastname: Cheong
authors.forename: Y C
authors.initials: YC
authors.lastname: Tan
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: R
authors.initials: R
authors.lastname: Jayaraman
authors.forename: A D
authors.initials: AD
authors.lastname: William
authors.forename: E T
authors.initials: ET
authors.lastname: Sun
authors.forename: B W
authors.initials: BW
authors.lastname: Dymock
authors.forename: K H
authors.initials: KH
authors.lastname: Ong
authors.forename: K
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: F
authors.initials: F
authors.lastname: Burrows
authors.forename: J M
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C570909:14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; D018844:Cyclin-Dependent Kinases