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http://ir.nhri.org.tw/handle/3990099045/12290
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| Title: | Discovery of a furanopyrimidine-based epidermal growth factor receptor inhibitor (DBPR112) as a clinical candidate for the treatment of non-small cell lung cancer |
| Authors: | Lin, SY;Chang Hsu, Y;Peng, YH;Ke, YY;Lin, WH;Sun, HY;Shiao, HY;Kuo, FM;Chen, PY;Lien, TW;Chen, CH;Chu, CY;Wang, SY;Yeh, KC;Chen, CP;Hsu, TA;Wu, SY;Yeh, TK;Chen, CT;Hsieh, HP |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| Abstract: | Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan. |
| Date: | 2019-11-27 |
| Relation: | Journal of Medicinal Chemistry. 2019 Nov 27;62(22):10108-10123. |
| Link to: | http://dx.doi.org/10.1021/acs.jmedchem.9b00722 |
| 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:000500420100007 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85075574489 |
| Appears in Collections: | [謝興邦] 期刊論文
[陳炯東] 期刊論文
[葉燈光] 期刊論文
[徐祖安] 期刊論文
[伍素瑩] 期刊論文
[林書玉] 期刊論文
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| NBP2019112001.pdf | | 5444Kb | Adobe PDF | 399 | View/Open |
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