TG101348 (SAR302503) --- JAK2 and BRD4 Dual Inhibitor

TG101348 is a potent, specific and orally bioavailable inhibitor of JAK2 (IC50 ~3 nM) and BRD4 (IC50 ~164 nM). It is 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. It also significantly inhibits JAK2 V617F, Flt3, and Ret with IC50 of 3 nM, 15 nM, and 48 nM, respectively. TG101348 induces apoptosis in both HEL and Ba/F3 JAK2V617F cells, but not in normal human dermal fibroblasts at concentrations up to 10 uM, and its antiproliferative IC50 against fibroblasts is > 5 uM. In a UT7/EPO cell line, TG101348 inhibited STAT5 phosphorylation at 600 nM and inhibited AKT phosphorylation while reducing GATA-1 S310 phosphorylation. It also displaces BRD4 from chromatin and suppresses c-Myc expression. The combination of inhibitory activities on independent kinase and bromodomain oncogenic pathways exemplifies a new strategy for rational single-agent polypharmacological targeting.

Product information

CAS Number: 936091-26-8

Molecular Weight: 524.68

Formula: C27H36N6O3S

Synonym:

Fedratinib

Related CAS Number:

1374744-69-0 (HCl hydrate)

Chemical Name: N-(tert-butyl)-3-((5-methyl-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

Smiles: CC1=CN=C(NC2C=CC(=CC=2)OCCN2CCCC2)N=C1NC1=CC(=CC=C1)S(=O)(=O)NC(C)(C)C

InChiKey: JOOXLOJCABQBSG-UHFFFAOYSA-N

InChi: InChI=1S/C27H36N6O3S/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 mM

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: ≥12 months 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

In Vitro:

TG101348 was used at 1 µM in vitro.

In Vivo:

TG101348 was dosed to mice orally at 120 mg/kg twice per day in xenograft models.

References:

1. Wernig G, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. (2008) Cancer Cell. 13(4):311-20.
2. Geron I, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. (2008) Cancer Cell. 13(4):321-30.
3. Lasho T, et al. Inhibition of JAK-STAT signaling by TG101348: a novel mechanism for inhibition of KITD816V-dependent growth in mast cell leukemia cells. (2010) Leukemia. 24(7):1378-80.
4. Ciceri P, et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. (2014) Nat Chem Biol. In press.

Products are for research use only. Not for human use.

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