MedKoo product information:

  TG-02

Description of TG-02:  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. 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). TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias. (source: Leukemia. 2012 Feb;26(2):236-43.)

Current developer:    Tragara Pharmaceuticals, Inc./S*BIO Pte Ltd,

TG02 was shown to be a 10-50nM inhibitor of CDKs 1,2,7 and 9 and other ongogenic kinases, including FLT3, JAK2 and ERK5. TG02 potently inhibits proliferation across a broad panel of human solid tumor cell lines (n = 15, IC50 from 64 to 504 nM). This potency exceeded that of other pan-CDK inhibitors currently in clinical development (SNS-032 and seliciclib) and other drugs that block FLT3 and JAK2 but lack CDK activity (sunitinib and TG101348), suggesting that the unique spectrum of kinases inhibited by TG02 may provide enhanced antitumor activity in solid tumors. TG02 potently induced G2/M cell cycle arrest that rapidly progressed to robust apoptosis in HCT116 cells and synergized with doxorubicin in pancreatic and breast cancer cell lines and with gemcitabine in ovarian carcinoma cells. TG02 was cleared from the blood within 8 hours of PO dosing but was retained in tumor masses at supratherapeutic levels for 24-48 h, depending on dose. Accordingly, pathway-related biomarkers were markedly suppressed for 24-72 h after dosing. In mice bearing SC HCT116 xenografts, TG02 inhibited tumor growth by 82% (p<0.001) at 75 mg/kg PO Q2D. Conclusions: TG02 is a multi-kinase inhibitor with a previously unreported spectrum of targets that shows promising preclinical activity for the treatment of solid tumors in man. (source: J Clin Oncol 28, 2010 (suppl; abstr e13549)

1: 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. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2011 Aug 23. doi: 10.1038/leu.2011.218. [Epub ahead of print] PubMed PMID: 21860433.

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Related Patent.

1. Preparation of solid state forms of macrocyclic kinase inhibitors for treatment of cancers By Mansfield, Robert K.; Lawhon, Tracy; Dymock, Brian. From PCT Int. Appl. (2011), WO 2011097525 A1 20110811.

2. Preparation of heteroalkyl linked pyrimidine macrocycle derivatives as antiproliferative agents. By Blanchard, Stephanie; Ethirajulu, Kantharaj; Lee, Cheng Hsia Angeline; Nagaraj, Harish Kumar Mysore; Poulsen, Anders; Sun, Eric T.; Tan, Yee Ling Evelyn; Teo, Ee Ling; William, Anthony Deodaunia. From PCT Int. Appl. (2007), WO 2007058628 A1 20070524.