WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 406434
CAS#: 719277-26-6
Description: TG003 is a potent, ATP-competitive inhibitor of Clk-family kinases (IC50 values are 20, 200 and 15 nM for mClk1, 2 and 4 respectively and >10 μ M for mClk3). . TG003 inhibited SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression of Clk-mediated phosphorylation. TG003 also suppressed serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles, and Clk1/Sty-dependent alternative splicing in mammalian cells. Consistently, administration of TG003 rescued the embryonic defects induced by excessive Clk activity in Xenopus.
MedKoo Cat#: 406434
Name: TG003
CAS#: 719277-26-6
Chemical Formula: C13H15NO2S
Exact Mass: 249.08235
Molecular Weight: 249.3287
Elemental Analysis: C, 62.62; H, 6.06; N, 5.62; O, 12.83; S, 12.86
Related CAS #: 300801-52-9 719277-26-6.
Synonym: TG003; TG-003; TG 003.
IUPAC/Chemical Name: (Z)-1-(3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-ylidene)propan-2-one
InChi Key: BGVLELSCIHASRV-QPEQYQDCSA-N
InChi Code: InChI=1S/C13H15NO2S/c1-4-14-11-8-10(16-3)5-6-12(11)17-13(14)7-9(2)15/h5-8H,4H2,1-3H3/b13-7-
SMILES Code: CC(/C=C1SC2=CC=C(OC)C=C2N\1CC)=O
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | TG003 is an inhibitor of Clk1/Sty; inhibits Clk1 and Clk4 with IC50 values of 20 and 15 nM, respectively. |
| In vitro activity: | The effect of TG003 on exon 9 inclusion was dose dependent (Fig. 5c, d). Interestingly, CLK1 and CLK4 were upregulated in the neural lineages compared to iPSCs (Fig. 5e), suggesting that increased activity of these genes might be associated with the misplicing of mutated exon 9. Thus, treatment of SS-NPCs with TG003 increased the amount of FL mRNA of ATR. In line with this observation, the phosphorylation of CHK1 protein in SS-NPCs induced by DNA replication stress was recovered by TG003 treatment (Fig. 5f). Finally, this study investigated whether TG003 could alleviate the abnormal mitosis observed in SS-NPCs. As a result, TG003 successfully increased the frequency of mitotic cells with mitotic spindles of normal morphology (Fig. 5g). Overall, TG003, a CLK1/4 inhibitor, could rescue the missplicing of ATR to alleviate the abnormal mitotic spindle formation in SS-NPCs. Reference: J Hum Genet. 2019; 64(5): 445–458. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075875/ |
| In vivo activity: | Having established that TG003 has a strong effect on PC3 proliferation in vitro, this study tested the effectiveness of TG003 in vivo on PC3 xenografts. This study injected one million cells subcutaneously into the flanks of nude mice. When tumours reached 3 × 3 mm in diameter, a solution of TG003 calculated to give 50 µM final concentration in the mouse was injected intraperitoneally twice a week. After 29 days the untreated tumours reached the maximum permitted size of 12 mm and the experiment was terminated. The TG003 treatments clearly prevented the xenografts growing and the volumes of the tumours in treated animals did not increase (Fig. 5). Other than the clear inhibition of tumour growth, the injection of mice with TG003 bi-weekly did not cause any obvious adverse effects. Reference: Sci Rep. 2021; 11: 7963. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041776/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 27.97 | 112.18 | |
| Ethanol | 18.7 | 75.0 |
The following data is based on the product molecular weight 249.3287 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Ichisima J, Suzuki NM, Samata B, Awaya T, Takahashi J, Hagiwara M, Nakahata T, Saito MK. Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model. J Hum Genet. 2019 May;64(5):445-458. doi: 10.1038/s10038-019-0574-8. Epub 2019 Mar 8. PMID: 30846821; PMCID: PMC8075875. 2. Uzor S, Zorzou P, Bowler E, Porazinski S, Wilson I, Ladomery M. Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention. Gene. 2018 Sep 5;670:46-54. doi: 10.1016/j.gene.2018.05.095. Epub 2018 May 24. PMID: 29802995. 3. Uzor S, Porazinski SR, Li L, Clark B, Ajiro M, Iida K, Hagiwara M, Alqasem AA, Perks CM, Wilson ID, Oltean S, Ladomery MR. CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer. Sci Rep. 2021 Apr 12;11(1):7963. doi: 10.1038/s41598-021-86908-6. PMID: 33846420; PMCID: PMC8041776. 4. Quaresma PG, Weissmann L, Zanotto TM, Santos AC, de Matos AH, Furigo IC, Simabuco FM, Donato J Jr, Bittencourt JC, Lopes-Cendes I, Prada PO. Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis. Int J Obes (Lond). 2017 Feb;41(2):268-278. doi: 10.1038/ijo.2016.174. Epub 2016 Oct 13. PMID: 27733761. |
| In vitro protocol: | 1. Ichisima J, Suzuki NM, Samata B, Awaya T, Takahashi J, Hagiwara M, Nakahata T, Saito MK. Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model. J Hum Genet. 2019 May;64(5):445-458. doi: 10.1038/s10038-019-0574-8. Epub 2019 Mar 8. PMID: 30846821; PMCID: PMC8075875. 2. Uzor S, Zorzou P, Bowler E, Porazinski S, Wilson I, Ladomery M. Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention. Gene. 2018 Sep 5;670:46-54. doi: 10.1016/j.gene.2018.05.095. Epub 2018 May 24. PMID: 29802995. |
| In vivo protocol: | 1. Uzor S, Porazinski SR, Li L, Clark B, Ajiro M, Iida K, Hagiwara M, Alqasem AA, Perks CM, Wilson ID, Oltean S, Ladomery MR. CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer. Sci Rep. 2021 Apr 12;11(1):7963. doi: 10.1038/s41598-021-86908-6. PMID: 33846420; PMCID: PMC8041776. 2. Quaresma PG, Weissmann L, Zanotto TM, Santos AC, de Matos AH, Furigo IC, Simabuco FM, Donato J Jr, Bittencourt JC, Lopes-Cendes I, Prada PO. Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis. Int J Obes (Lond). 2017 Feb;41(2):268-278. doi: 10.1038/ijo.2016.174. Epub 2016 Oct 13. PMID: 27733761. |
1: Li P, Carter G, Romero J, Gower KM, Watson J, Patel NA, Cooper DR. Clk/STY (cdc2-like kinase 1) and Akt regulate alternative splicing and adipogenesis in 3T3-L1 pre-adipocytes. PLoS One. 2013;8(1):e53268. doi: 10.1371/journal.pone.0053268. Epub 2013 Jan 4. PubMed PMID: 23308182; PubMed Central PMCID: PMC3537621.
2: Ninomiya K, Kataoka N, Hagiwara M. Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor. J Cell Biol. 2011 Oct 3;195(1):27-40. doi: 10.1083/jcb.201107093. Epub 2011 Sep 26. PubMed PMID: 21949414; PubMed Central PMCID: PMC3187705.
3: Nishida A, Kataoka N, Takeshima Y, Yagi M, Awano H, Ota M, Itoh K, Hagiwara M, Matsuo M. Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nat Commun. 2011;2:308. doi: 10.1038/ncomms1306. PubMed PMID: 21556062; PubMed Central PMCID: PMC3113229.
4: Rosenthal AS, Tanega C, Shen M, Mott BT, Bougie JM, Nguyen DT, Misteli T, Auld DS, Maloney DJ, Thomas CJ. Potent and selective small molecule inhibitors of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine-phosphorylation-regulated kinases (Dyrk). Bioorg Med Chem Lett. 2011 May 15;21(10):3152-8. doi: 10.1016/j.bmcl.2011.02.114. Epub 2011 Mar 4. PubMed PMID: 21450467; PubMed Central PMCID: PMC3085634.
5: James BP, Staatz WD, Wilkinson ST, Meuillet E, Powis G. Superoxide dismutase is regulated by LAMMER kinase in Drosophila and human cells. Free Radic Biol Med. 2009 Mar 15;46(6):821-7. doi: 10.1016/j.freeradbiomed.2008.12.012. Epub 2008 Dec 24. PubMed PMID: 19135146; PubMed Central PMCID: PMC2699669.
6: Yomoda J, Muraki M, Kataoka N, Hosoya T, Suzuki M, Hagiwara M, Kimura H. Combination of Clk family kinase and SRp75 modulates alternative splicing of Adenovirus E1A. Genes Cells. 2008 Mar;13(3):233-44. doi: 10.1111/j.1365-2443.2008.01163.x. PubMed PMID: 18298798.
7: Muraki M, Ohkawara B, Hosoya T, Onogi H, Koizumi J, Koizumi T, Sumi K, Yomoda J, Murray MV, Kimura H, Furuichi K, Shibuya H, Krainer AR, Suzuki M, Hagiwara M. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem. 2004 Jun 4;279(23):24246-54. Epub 2004 Mar 8. PubMed PMID: 15010457.
