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 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
Chemical Name: N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)benzenesulfonamide
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)
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
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.
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.
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.
Products are for research use only. Not for human use.
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