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|Ref Type||Journal Article|
|Authors||Yang H, Lawrence HR, Kazi A, Gevariya H, Patel R, Luo Y, Rix U, Schonbrunn E, Lawrence NJ, Sebti SM|
|Title||Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.|
|Date||2014 May 30|
|Abstract Text||Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. Importantly, we have developed dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, AJI-100 caused regression of human tumor xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each kinase alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AJI-100||Aurka Inhibitors 23 Aurkb Inhibitors 18 JAK2 Inhibitor 17||AJI-100 is a dual-AURKA/B, JAK2 inhibitor, which prevents cell growth and induces apoptosis (PMID: 24930769, PMID: 28077684).|
|AJI-214||Aurka Inhibitors 23 Aurkb Inhibitors 18 JAK2 Inhibitor 17||AJI-214 is a dual-AURKA/B, JAK2 inhibitor, which prevents cell growth and induces apoptosis (PMID: 24930769, PMID: 28077684).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||breast cancer||not applicable||AJI-214||Preclinical - Cell culture||Actionable||In a preclinical study, AJI-214 inhibited invasion and induced apoptosis of breast cancer cells in culture (PMID: 24930769).||24930769|
|Unknown unknown||breast cancer||not applicable||AJI-100||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, AJI-100 induced apoptosis and inhibited cell growth of breast cancer cell lines and xenografts (PMID: 24930769).||24930769|