TG02   Click here for help

GtoPdb Ligand ID: 9095

Synonyms: compound 26h [PMID: 22148278] | SB-1317 | SB1317 | TG-02 | zotiraciclib (proposed INN)
Compound class: Synthetic organic
Comment: TG02 is an orally active multi-kinase inhibitor, with a unique activity profile against CDKs, JAK2 and FLT3 [4-5]. Like pacritinib it is a small molecule macrocycle. TG02 was rationally designed to inhibit several key signaling pathways simultaneously with the aim of maximising anti-cancer efficacy. It is being investigated for its anti-leukemic potential [2-3].
The compound is administered as the citrate salt.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 4
Hydrogen bond donors 1
Rotatable bonds 0
Topological polar surface area 50.28
Molecular weight 372.2
XLogP 4.29
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CN1CC=CCCOc2cccc(c2)c2nc(Nc3cc(C1)ccc3)ncc2
Isomeric SMILES CN1C/C=C/CCOc2cccc(c2)c2nc(Nc3cc(C1)ccc3)ncc2
InChI 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+
InChI Key VXBAJLGYBMTJCY-NSCUHMNNSA-N
Bioactivity Comments
In a kinase profiling study TG02 was found to inhibit 17 of the 63 kinases tested [1]. Eleven of the 17 positive hits were against CDK/JAK/FLT family members. Some of the other kinases inhibited by TG02 are implicated in inflammatory and proliferative processes (e.g. Lck, Fyn, Fms (CSF1R), TYRO3, ERK5, and p38δ). TG02 most potently inhibited CDK isoforms (IC50s 3-9 nM for CDKs 1,2,3,5 and 9 and IC50 of 37 nM for CDK7). CDK6 was less potently inhibited (IC50 113 nM). CDK4 was not significantly inhibited. The Janus kinase family members JAK1, JAK2 and TYK2 were potently inhibited but JAK3 was not. Class III receptor tyrosine kinases Fms and Fms-like tyrosine kinase 3 (FLT3) were potently inhibited, as were the src family kinases Lck and Fyn (but not Src itself), and the MAPK family members ERK5 and p38δ.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin dependent kinase 9 Hs Inhibitor Inhibition 8.5 pIC50 - 1
pIC50 8.5 (IC50 3x10-9 M) [1]
cyclin dependent kinase 5 Hs Inhibitor Inhibition 8.4 pIC50 - 1
pIC50 8.4 (IC50 4x10-9 M) [1]
cyclin dependent kinase 3 Hs Inhibitor Inhibition 8.1 pIC50 - 1
pIC50 8.1 (IC50 8x10-9 M) [1]
cyclin dependent kinase 2 Hs Inhibitor Inhibition 7.9 – 8.3 pIC50 - 1,5
pIC50 7.9 – 8.3 (IC50 1.3x10-8 – 5x10-9 M) [1,5]
cyclin dependent kinase 1 Hs Inhibitor Inhibition 8.1 pIC50 - 1
pIC50 8.1 (IC50 9x10-9 M) [1]
tyrosine kinase 2 Hs Inhibitor Inhibition 7.8 pIC50 - 1
pIC50 7.8 (IC50 1.4x10-8 M) [1]
Janus kinase 2 Hs Inhibitor Inhibition 7.1 – 7.7 pIC50 - 1,5
pIC50 7.1 – 7.7 (IC50 7.3x10-8 – 1.9x10-8 M) [1,5]
Janus kinase 1 Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 5.9x10-8 M) [1]
Selectivity at catalytic receptors
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
colony stimulating factor 1 receptor Hs Inhibitor Inhibition 7.6 pIC50 - 1
pIC50 7.6 (IC50 2.7x10-8 M) [1]
fms related receptor tyrosine kinase 3 Hs Inhibitor Inhibition 7.3 – 7.7 pIC50 - 1,5
pIC50 7.3 – 7.7 (IC50 5.6x10-8 – 1.9x10-8 M) [1,5]