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| 題名: | Discovery of clinical candidate DBPR112, a furanopyrimidine-based epidermal growth factor receptor inhibitor for the treatment of non-small cell lung cancer |
| 作者: | Hsieh, HP;Chang, JY;Yeh, CT;Lin, SY;Ke, YY;Lin, WH;Hsu, TA;Wu, SY;Yeh, TK |
| 貢獻者: | Institute of Biotechnology and Pharmaceutical Research |
| 摘要: | Background: Lung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations. Methods: We introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage. Results: We optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation. Conclusions: X-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan. |
| 日期: | 2019-10 |
| 關聯: | Annals of Oncology. 2019 Oct;30(Suppl. 5):789. |
| Link to: | https://doi.org/10.1093/annonc/mdz268.089 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000491295505228 |
| 顯示於類別: | [葉燈光] 會議論文/會議摘要
[伍素瑩] 會議論文/會議摘要
[徐祖安] 會議論文/會議摘要
[謝興邦] 會議論文/會議摘要
[林書玉] 會議論文/會議摘要
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