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Ref Type Journal Article
PMID (21860433)
Authors Goh KC, Novotny-Diermayr V, Hart S, Ong LC, Loh YK, Cheong A, Tan YC, Hu C, Jayaraman R, William AD, Sun ET, Dymock BW, Ong KH, Ethirajulu K, Burrows F, Wood JM
Title TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties.
Journal Leukemia
Vol 26
Issue 2
Date 2012 Feb
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Zotiraciclib Zotiraciclib 3 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Zotiraciclib SB1317|TG02 CDK1 Inhibitor 13 CDK2 Inhibitor 19 CDK5 Inhibitor 8 CDK7 Inhibitor 13 CDK9 Inhibitor 17 FLT3 Inhibitor 55 JAK2 Inhibitor 17 Zotiraciclib (TG02) is a pyrimidine-based molecule that inhibits CDK1, CDK2, CDK3, CDK5, CDK7, CDK9, JAK2, and FLT3, which results in growth inhibition in tumor cells (PMID: 21860433).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 mutant acute myeloid leukemia sensitive Zotiraciclib Preclinical - Cell line xenograft Actionable In a preclinical study, Zotiraciclib (TG02) inhibited growth of FLT3-mutated acute myeloid leukemia cells in culture, resulted in complete tumor regression in cell line xenograft animal models (PMID: 21860433). 21860433
Unknown unknown acute myeloid leukemia not applicable Zotiraciclib Preclinical - Patient cell culture Actionable In a preclinical study, Zotiraciclib (TG02) inhibited growth of acute myeloid leukemia cell lines and patient-derived acute myeloid leukemia cells in culture (PMID: 21860433). 21860433
Unknown unknown acute lymphoblastic leukemia not applicable Zotiraciclib Preclinical - Cell culture Actionable In a preclinical study, TG02 inhibited growth of acute lymphocytic leukemia cells in culture (PMID: 21860433). 21860433