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제125회 대한화학회 학술발표회 및 총회 Identification of novel allosteric inhibitors of AurkA

2020년 2월 6일 10시 37분 13초
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Medicinal Chemistry
저자 및
Euijung Kim, Wooyoung Hur1,*
Department of Chemistry, Korea University, Korea
1Chemical Kinomics Research Center, Korea Institute of Science and Technology, Korea
Aurora kinases are a family of cell division regulators that govern the correct assembly of a bipolar mitotic spindle and the fidelity of chromosome segregation. Their overexpression is associated with genomic instability and aneuploidy, and is frequently observed in cancer. Accordingly, competitive inhibitors targeting Aurora kinase activity at the ATP-binding site are being investigated for therapeutic purposes. Despite promising pre-clinical data, these molecules display moderate effects in clinical trials and incomplete selectivity. As an alternative approach, protein-protein interaction inhibitors targeting mitotic kinases and their activators can be exploited to achieve increased specificity of action. In this study, a virtual screening of small molecules against the TPX2 interaction site, which also acts as the allosteric site, of AurkA led to the identification of 40 potential inhibitors. in vitro AurkA assay confirmed that a unique scaffold-containing hit (B6) inhibits Aurora-A in the low micromolar range. We prepared several B6 analogues and found an improved, equipotent activity from 3 analogues against both wild-type and drug-resistant mutant (G216L) of AurkA. The identified novel allosteric inhibitors of AurkA are in a further optimization towards anti-cancer drugs.