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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/13435


    Title: Discovery and synthesis of a pyrimidine-based aurora kinase inhibitor to reduce levels of MYC oncoproteins
    Authors: Chi, YH;Yeh, TK;Ke, YY;Lin, WH;Tsai, CH;Wang, WP;Chen, YT;Su, YC;Wang, PC;Chen, YF;Wu, ZW;Yeh, JY;Hung, MC;Wu, MH;Wang, JY;Chen, CP;Song, JS;Shih, C;Chen, CT;Chang, CP
    Contributors: Institute of Biotechnology and Pharmaceutical Research
    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 (IC(50) < 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.
    Date: 2021-05-19
    Relation: Journal of Medicinal Chemistry. 2021 May 19;64(11):7312-7330.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.0c01806
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000662187100014
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85108021102
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