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Ref Type | Journal Article | ||||||||||||
PMID | (24930769) | ||||||||||||
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. | ||||||||||||
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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 |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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AJI-100 | Aurka Inhibitors 26 Aurkb Inhibitors 21 JAK2 Inhibitor 16 | AJI-100 is a dual-AURKA/B, JAK2 inhibitor, which prevents cell growth and induces apoptosis (PMID: 24930769, PMID: 28077684). | ||
AJI-214 | Aurka Inhibitors 26 Aurkb Inhibitors 21 JAK2 Inhibitor 16 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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