Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelofibrosis (MF) is subtype of myeloproliferative neoplasm (MPN) characterized by a relatively poor prognosis in patients. Understanding the factors that drive MF pathogenesis is crucial to identifying novel therapeutic approaches with the potential to improve patient care. Driver mutations in three main genes (janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL)) are recurrently mutated in MPN and are sufficient to engender MPN using animal models. Interestingly, animal studies have shown that the underlying molecular mutation and the acquisition of additional genetic lesions is associated with MF outcome and transition from early stage MPN such as essential thrombocythemia (ET) and polycythemia vera (PV) to secondary MF. In this issue, we review murine models that have contributed to a better characterization of MF pathobiology and identification of new therapeutic opportunities in MPN.
 ...
PMID:Murine Models of Myelofibrosis. 3284

Somatic mutations of calreticulin (CALR)have been identified as one of the main disease drivers of myeloproliferative neoplasms (MPNs), suggesting that developing drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD)abolishes the ability of mutant CALRto oncogenically activate the thrombopoietin receptor (MPL).We thus hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in-silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing selective growth inhibitory effect on cells that depend on oncogenic CALRs for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR mutated cells than in CALR wild type cells. Additionally, knockout or C-terminal truncation of CALR abolished the drug hypersensitivity in CALR mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, the disruption of the mutant CALR-MPL interaction, the inhibition of the JAK2-STAT5 pathway, and reduction of intracellular level of mutant CALR upon the drug treatment. Our data conclude that small molecules targeting the GBD of CALR can selectively kill CALR mutated cells by disrupting the CALR-MPL interaction and inhibiting the oncogenic signaling.
 ...
PMID:Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor. 3320 18


<< Previous 1 2 3 4 5 6 7 8 9