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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.
Journal Oncotarget
Vol 5
Issue 10
Date 2014 May 30
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AJI-100 AJI-100 1 0
AJI-214 AJI-214 1 0
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