TG101209 936091-14-4

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Molecular Weight:

509.67 TG101209 is a selective JAK2 inhibitor with IC50 of 6 nM, less potent to Flt3 and RET with IC50 of 25 nM and 17 nM, ~30-fold selective for JAK2 than JAK3, sensitive to JAK2V617F and MPLW515L/K mutations.


Biological Activity


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
B200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell
line, TG101209 inducs 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 triggered apoptosis of
transformed Ba/F3 cells.


100 mg/kg of TG101209 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%.






Cell-free Kinase Activity Assays


IC50 values for TG101209 are determined using a luminescence-based
kinase assay with recombinant JAK2, VEGFR2/KDR, and JAK3 obtained from
Upstate Cell Signaling Solutions. Kinase reactions are carried out in a
buffer consisting of 40mM Tris buffer (pH 7.4), 50mM MgCl2,
800M EGTA, 350M Triton X-100, 2M -mercaptoethanol, 100M peptide
substrate, and an appropriate amount of JAK2, VEGFR2/KDR or JAK3 such
that the assay is linear over 60 minutes.


The reaction is initiated by
the addition of 10L of ATP to a final concentration of 3mM and
terminated by the addition of Kinase-Glo reagent after 60 minutes.
Luciferase activity is quantified using an Ultra 384 instrument set for
luminosity measurements. IC50 values are derived from experimental data
using the non-linear curve fitting capabilities of the GraphPad Prism
4.0 software. The single concentration inhibition data for a panel of 63
kinases is determined using the SelectScreen TM service.






Method


In brief, approximately 2 × 103 cells are plated into
microtiterplate wells in 100 ml RPMI-1640 growth media with indicated
concentrations of TG101209. The relative growth of cells is quantified
at 24-hour intervals using Cell Proliferation Kit II (XTT) as per
manufacturer's guidelines. After incubation, 20 mL of XTT is added to
the wells and allowed to incubate for 4-6 hours.


The colored formazan
product is measured spectrophotometrically at 450 nm with correction at
650 nm, and IC50 values are determined using the GraphPad Prism 4.0
software. Data are subjected to a non-linear regression-fit analysis and
IC50 values are determined as the concentration that inhibited
proliferation by 50%. All experiments are done in triplicate and the
results normalized to growth of untreated cells.

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Product Categories : Protein Tyrosine Kinase > FLT3 Inhibitor