TG101209
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MedKoo CAT#: 406190

CAS#: 936091-14-4

Description: TG101209 is a novel and potent JAK2 inhibitor, which induced dose- and time-dependent cytotoxicity in a variety of multiple myeloma (MM) cell lines. The induction of cytotoxicity was associated with inhibition of cell cycle progression and induction of apoptosis in myeloma cell lines and patient-derived plasma cells. Exploring the mechanism of action of TG101209 indicated downregulation of pJak2, pStat3, and Bcl-xl levels with upregulation of pErk and pAkt levels indicating cross talk between signaling pathways. TG101209 , when used in combination with the PI3K inhibitor LY294002, demonstrated synergistic cytotoxicity against myeloma cells.


Chemical Structure

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TG101209
CAS# 936091-14-4

Theoretical Analysis

MedKoo Cat#: 406190
Name: TG101209
CAS#: 936091-14-4
Chemical Formula: C26H35N7O2S
Exact Mass: 509.25729
Molecular Weight: 509.67
Elemental Analysis: C, 61.27; H, 6.92; N, 19.24; O, 6.28; S, 6.29

Price and Availability

Size Price Availability Quantity
25.0mg USD 90.0 Ready to ship
50.0mg USD 150.0 Ready to ship
100.0mg USD 250.0 Ready to ship
200.0mg USD 450.0 Ready to ship
500.0mg USD 950.0 Ready to ship
1.0g USD 1650.0 Ready to ship
2.0g USD 2850.0 Ready to ship
5.0g USD 4250.0 2 Weeks
10.0g USD 7650.0 2 Weeks
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Synonym: TG101209; TG-101209; TG 101209

IUPAC/Chemical Name: N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide

InChi Key: JVDOKQYTTYUYDV-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H35N7O2S/c1-19-18-27-25(29-20-9-11-22(12-10-20)33-15-13-32(5)14-16-33)30-24(19)28-21-7-6-8-23(17-21)36(34,35)31-26(2,3)4/h6-12,17-18,31H,13-16H2,1-5H3,(H2,27,28,29,30)

SMILES Code: O=S(C1=CC=CC(NC2=NC(NC3=CC=C(N4CCN(C)CC4)C=C3)=NC=C2C)=C1)(NC(C)(C)C)=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: TG101209 is a JAK2 inhibitor with IC50 of 6 nM.
In vitro activity: The DU 528, HSD2, PEER, MOLT-4 and Jurkat T-ALL cell lines were treated with TG101209, and cell proliferation was analysed using MTT assay. The IC50s of the cell lines were 2.542 µM (DU528), 0.329 µM (HSD2), 0.612 µM (PEER), 2.893 µM (MOLT-4) and 1.794 µM (Jurkat) (Supplementary Figure 2). Apoptosis was increased in the HSD2 and PEER cell lines in a TG101209 concentration-dependent manner, according to the flow cytometry analysis. The expression of apoptosis-related proteins (Bax, Cleaved PARP, caspase-3 and caspase-9) was determined by Western blotting. The expression levels of Bax and Cleaved PARP were up-regulated by TG101209, while caspase-3 and caspase-9 were down-regulated in both HSD2 and PEER cell lines (Figure 3A). The cell cycle of each cell line was analysed using flow cytometry. After treatment, the cell cycle was arrested mainly at the G2/M phase. The expression of the indicated cell cycle-related proteins (P21, P27, CDK4 and CDK6) was determined by Western blotting. The expression levels of P21 and P27 were up-regulated by TG101209, while those of CDK4 and CDK6 were down-regulated by TG101209 in both the HSD2 and PEER cell lines (Figure 3B). Primary bone marrow cells from T-ALL patients and healthy controls were treated with TG101209 (0, 1, 2, 4, 6, 8, or 10 μM), and cell proliferation was analysed using MTT assay. The IC50s were 0.755um and 1.565 um respectively. (Supplementary Figure 2). Apoptosis was increased in the cells in a TG101209 concentration-dependent manner, according to the flow cytometry analysis. (Figure 3A). Reference: Oncotarget. 2017 Oct 23;8(63):106753-106763. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739771/
In vivo activity: To test the in vivo efficacy of TG101209 in inhibiting JAK2V617F, a mouse model of JAK2V617F-induced hematopoietic disease was used. All the animals in the control group died due to disease progression by day 11. In striking contrast, TG101209 at the highest dose level (100 mg/kg b.i.d.) was effective in treating JAK2V617F-induced disease as there was a statistically significant prolongation of survival in this group (10 days; P<0.02), and the animals in this group were still alive at the previously defined study end point of 10 days past the time of death of the final placebo-treated animal (Figure 6a). The animals at the lower dose levels (that is, 10 or 30 mg/kg b.i.d.) developed disease with the same latency and penetrance as the placebo-treated animals, without evidence of prolongation of survival (Figure 6a). Compared with placebo-treated animals, TG101209-treated animals exhibited a statistically significant, dose-dependent reduction in the circulating tumor cell burden at day +11 (75% GFP+ cells in placebo-treated versus 15% GFP+ cells in 100 mg/kg b.i.d. TG101209-treated animals; P<0.02) (Figure 6b). The clinical benefit of TG101209 in this model correlated with inhibition of JAK2V617F activity in vivo, evident in the marked decrease in STAT-5 phosphorylation demonstrable in splenic tumors, as early as 7 h after administration of a single dose of TG101209 (100 mg/kg) to the affected mice (Figure 6c). Reference: Leukemia. 2007 Aug;21(8):1658-68. https://www.nature.com/articles/2404750

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 16.0 31.39
DMSO 29.17 57.23
DMF:PBS (pH 7.2) (1:1) 0.5 0.98
Ethanol 0.12 0.24

Preparing Stock Solutions

The following data is based on the product molecular weight 509.67 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.

Recalculate based on batch purity %
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. Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, Pardanani A, Tefferi A, Rajkumar SV, Kumar S. TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol. 2010 Sep;85(9):675-86. doi: 10.1002/ajh.21785. PMID: 20652971; PMCID: PMC2940994. 2. Cheng Z, Yi Y, Xie S, Yu H, Peng H, Zhang G. The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling. Oncotarget. 2017 Oct 23;8(63):106753-106763. doi: 10.18632/oncotarget.22053. PMID: 29290986; PMCID: PMC5739771. 3. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007 Aug;21(8):1658-68. doi: 10.1038/sj.leu.2404750. Epub 2007 May 31. PMID: 17541402. 4. Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP, Lu B. Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 2011 Apr;6(4):699-706. doi: 10.1097/JTO.0b013e31820d9d11. PMID: 21325979; PMCID: PMC3104103.
In vitro protocol: 1. Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, Pardanani A, Tefferi A, Rajkumar SV, Kumar S. TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol. 2010 Sep;85(9):675-86. doi: 10.1002/ajh.21785. PMID: 20652971; PMCID: PMC2940994. 2. Cheng Z, Yi Y, Xie S, Yu H, Peng H, Zhang G. The effect of the JAK2 inhibitor TG101209 against T cell acute lymphoblastic leukemia (T-ALL) is mediated by inhibition of JAK-STAT signaling and activation of the crosstalk between apoptosis and autophagy signaling. Oncotarget. 2017 Oct 23;8(63):106753-106763. doi: 10.18632/oncotarget.22053. PMID: 29290986; PMCID: PMC5739771.
In vivo protocol: 1. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007 Aug;21(8):1658-68. doi: 10.1038/sj.leu.2404750. Epub 2007 May 31. PMID: 17541402. 2. Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP, Lu B. Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 2011 Apr;6(4):699-706. doi: 10.1097/JTO.0b013e31820d9d11. PMID: 21325979; PMCID: PMC3104103.

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1: Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP, Lu B. Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 2011 Apr;6(4):699-706. doi: 10.1097/JTO.0b013e31820d9d11. PubMed PMID: 21325979; PubMed Central PMCID: PMC3104103.

2: Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, Pardanani A, Tefferi A, Rajkumar SV, Kumar S. TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol. 2010 Sep;85(9):675-86. doi: 10.1002/ajh.21785. PubMed PMID: 20652971; PubMed Central PMCID: PMC2940994.

3: Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, Joshi A, Balusu R, Koul S, Chen J, Savoie A, Ustun C, Jillella AP, Atadja P, Levine RL, Bhalla KN. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009 Dec 3;114(24):5024-33. doi: 10.1182/blood-2009-05-222133. Epub 2009 Oct 14. PubMed PMID: 19828702; PubMed Central PMCID: PMC2788976.

4: Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007 Aug;21(8):1658-68. Epub 2007 May 31. PubMed PMID: 17541402.



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