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MedKoo CAT#: 205642
Description: TG02, also known as SB1317, is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. 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.
MedKoo Cat#: 205642
Name: TG02 (SB1317)
Chemical Formula: C23H24N4O
Exact Mass: 372.19501
Molecular Weight: 372.46
Elemental Analysis: C, 74.17; H, 6.49; N, 15.04; O, 4.30
Synonym: TG02; TG 02; TG02; SB1317; SB1317; SB 1317.
IUPAC/Chemical Name: 20-Oxa-5,7,14,27-tetraazatetracyclo[220.127.116.11,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene, 14-methyl-
InChi Key: VXBAJLGYBMTJCY-NSCUHMNNSA-N
InChi Code: InChI=1S/C23H24N4O/c1-27-13-3-2-4-14-28-21-10-6-8-19(16-21)22-11-12-24-23(26-22)25-20-9-5-7-18(15-20)17-27/h2-3,5-12,15-16H,4,13-14,17H2,1H3,(H,24,25,26)/b3-2+
SMILES Code: CN(C/C=C/CCO1)CC2=CC(NC3=NC(C4=CC1=CC=C4)=CC=N3)=CC=C2
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: Pallis M, Abdul-Aziz A, Burrows F, Seedhouse C, Grundy M, Russell N. The multi-kinase inhibitor TG02 overcomes signalling activation by survival factors to deplete MCL1 and XIAP and induce cell death in primary acute myeloid leukaemia cells. Br J Haematol. 2012 Oct;159(2):191-203. doi: 10.1111/bjh.12018. Epub 2012 Aug 30. PubMed PMID: 22934750.
2: Poulsen A, William A, Blanchard S, Nagaraj H, Williams M, Wang H, Lee A, Sun E, Teo EL, Tan E, Goh KC, Dymock B. Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3). J Mol Model. 2013 Jan;19(1):119-30. doi: 10.1007/s00894-012-1528-7. Epub 2012 Jul 22. PubMed PMID: 22820730.
3: Pasha MK, Jayaraman R, Reddy VP, Yeo P, Goh E, Williams A, Goh KC, Kantharaj E. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42. PubMed PMID: 22372550.
4: William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[18.104.22.168(2,6).1(8,12)]heptaco sa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer. J Med Chem. 2012 Jan 12;55(1):169-96. doi: 10.1021/jm201112g. Epub 2011 Dec 29. PubMed PMID: 22148278.
5: 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. 2012 Feb;26(2):236-43. doi: 10.1038/leu.2011.218. Epub 2011 Aug 23. PubMed PMID: 21860433.