TG101348 is an inhibitor of Janus kinase 2 (JAK2) with an IC₅₀ of 6 nM. It also inhibits related kinases fms-related tyrosine kinase 3 (FLT3), RET, and JAK3 with less potent activity, having IC₅₀ values of 25, 17 and 169 nM, respectively (Pardanani et al.). It is proposed to bind to the ATP binding pocket of its kinase targets (Zhou et al.).
CANCER RESEARCH
· Inhibits growth of Ba/F3 cells expressing JAK2 V617F or MPL W515L mutations (Pardanani et al.).
· Reduces tumor cell burden and increases survival in mouse models of JAK2 V617F-induced hematopoietic and myeloproliferative disease (Pardanani et al.; Wernig et al.).
· Sensitizes erlotinib-resistant non-small cell lung cancer cells to erlotinib treatment in vitro and in a mouse xenograft model (Zhang et al.).
· Displaces BRD4 from chromatin and suppresses c-MYC expression in multiple myeloma cells in vitro (Ciceri et al.).
CANCER RESEARCH
· Inhibits growth of Ba/F3 cells expressing JAK2 V617F or MPL W515L mutations (Pardanani et al.).
· Reduces tumor cell burden and increases survival in mouse models of JAK2 V617F-induced hematopoietic and myeloproliferative disease (Pardanani et al.; Wernig et al.).
· Sensitizes erlotinib-resistant non-small cell lung cancer cells to erlotinib treatment in vitro and in a mouse xenograft model (Zhang et al.).
· Displaces BRD4 from chromatin and suppresses c-MYC expression in multiple myeloma cells in vitro (Ciceri et al.).
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Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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Resources and Publications
Educational Materials (2)
Publications (5)
JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor. Oncotarget 2015
Abstract
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.
Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nature chemical biology 2014
Abstract
Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.
Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia 2014
Abstract
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