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.
CAS Number: 936091-14-4
Molecular Weight: 509.67
Chemical Name: N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥360 days if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
TG101209 is an orally bioavailable, small molecule, ATP-competitive inhibitor towards several tyrosine kinases. TG101209 inhibits growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC50 of 200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209 induces cell cycle arrest and apoptosis, and inhibits phosphorylation of JAK2V617F, STAT5 and STAT3. TG101209 suppresses growth of hematopoietic colonies from primary progenitor cells harboring JAK2V617F or MPL515 mutations. TG101209 significantly reduces STAT5 phosphorylation without affecting the total amount of STAT5 protein. TG101209 inhibits survivin and reduces phosphorylation of STAT3 in HCC2429 and H460 lung cancer cells. TG101209 results in radio sensitization of HCC2429 and H460 lung cancer cells in vitro. A recent study indicates TG101209 abrogates BCR-JAK2 and STAT5 phosphorylation, decreases Bcl-xL expression and triggers apoptosis of transformed Ba/F3 cells.
TG101209 (100 mg/kg) effectively prolongs the survival in JAK2V617F-induced disease (10 days). Compared with placebo-treated animals, TG101209-treated animals exhibit statistically significant, dose-dependent reduction in the circulating tumor cell burden at day +11 to 20%.
- 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.
- 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.
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