As is introduced previously, constitutive activation of STATs is the feature of many types of leukemia and solid tumors. The most common mechanism for constitutive activation of STAT factors is the dysregulation of tyrosine kinases. The V617F mutation of JAK2 is the first identified activating mutation caused by the disease, found in patients with myeloproliferative neoplasms (MPNs). Several JAK2 inhibitors targeted to JAK2 V617F are now under study for clinical trials of MPNs. However, the major drawback of tyrosine kinase inhibitor therapy is the development of secondary resistance resulted from the acquisition of new mutations. Previously, Hornakova and his lab members have built an in vitro model of BaF3 cell line with constitutive STAT5 activation, and these autonomous cells also show a cytokine-independent activation of JAK1 and STAT5. During selection of BaF3 autonomous clones, many mutations in kinase and pseudokinase domain of JAK1 spontaneously happens. Moreover, futher study shows that the JAK1 mutations occurring spontaneously in vitro were JAK1/STAT5-activating mutations. After the treatment with the JAK inhibitor INCB018424, the mutation targeting JAK1 Phe958, Pro960 and F958V confers resistance to ATP-competitive JAK inhibitors[1]. In fact, the mutants also happened on other signaling pathways. For example, the T790M mutation has been reported to activate the wild-type EGFR, acting both as a drug-resistance and as an activating mutation, similar to JAK mutations[2]. Therefore, these JAK mutants should be considered as an invaluable measure to evaluate the activity of novel, potentially more potent, ATP-competitive JAK inhibitors against MPNs and other cancer associated with JAK kinase mutations. As we all know, kinase inhibitors are often used in the treatment of cancer and inflammation, since multiple kinase pathways is critical for tumor growth, including those contributing to proliferation, angiogenesis and apoptotic regulation. In many cases, broad-spectrum inhibitors have been reported to yield superior efficacy compared with traditional agents, as exemplified by multi-kinase inhibitors such as sunitinib and sorafenib. As myeloproliferative neoplasms and acute myeloid leukemia (AML) continue to be incurable diseases in hematology, CDKs, JAK2 and FLT3 offer hope as novel targets for the development of innovative therapies. Synthetic macrocyclic organic compounds has great potential for pharmacological applications, but synthetic challenges and poor pharmacologic properties have limited their application. Thus, investigators have been studying to change the dilemma. Last week, in the journal of leukemia, Goh et al. reported a novel, small molecular synthetic macrocycle which can significantly inhibit activities of some CDKs, JAK2 and FLT3. As is shown in the table, TG02 is also a inhibitor with a spectrum of activities again multiple kinases. Assay on cell level showed that TG02 impaired tumor cells proliferation and induced cell apoptosis. Also, TG02 effectively blocked intracellular phosphorylation of substrates for CDK2, JAK2 and FLT3,and accordingly impaired the respected signaling pathways. Moreover, in animal models of AML, the efficacy of TG02 was initially tested that the tumor growth was inhibited when treated with TG02[1]. In summary, TG02 is a novel chemical agent with wide spectrum activity against oncogenic factors. TG02’s unique kinase spectrum and favorable pharmacological profile provide the potential therapy to patients with advanced leukemias Reference [1]. Haematologica 2011;96(6):845-853. [2]. Cancer Res 2007;67(15):7319-26. Related Post Mechanism of STAT3 constitutive activation in Szary syndrome
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