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• W3162339217 abstract "The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC." @default.
• W3162339217 created "2021-05-24" @default.
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• W3162339217 date "2021-05-19" @default.
• W3162339217 modified "2023-10-17" @default.
• W3162339217 title "Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins" @default.
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• W3162339217 doi "https://doi.org/10.1021/acs.jmedchem.0c01806" @default.
• W3162339217 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8279414" @default.
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• W3162339217 hasPublicationYear "2021" @default.
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