CC BY 4.0 · Pharmaceutical Fronts 2021; 03(01): e1-e7
DOI: 10.1055/s-0041-1731081
Original Article

Discovery of SIPI6473, a New, Potent, and Orally Bioavailable Multikinase Inhibitor for the Treatment of Non-small Cell Lung Cancer

Xiu Gu
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2  School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Zi-Xue Zhang
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Min-Ru Jiao
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Xin-Yan Peng
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Jian-Qi Li
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Qing-Wei Zhang
1  Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations
Funding This work was financially supported by the National Science and Technology Major Project (Grant No. 2018ZX09711002-002-009), the National Natural Science Foundation of China (Grant No. 81703358), and Science and Technology Commission of Shanghai Municipality (Grant No. 17431903900, 18QB1404200,18ZR1437700).


Abstract

A novel series of quinazoline derivatives were designed, synthesized, and evaluated as multikinase inhibitors. Most of these compounds showed antiproliferation activities of several human cancer cell lines and exhibited inhibition efficacy against the estimated glomerular filtration rate (EGFR) in the nanomolar level. Among those compounds, compound B5 (also named SIPI6473) displayed the maximum effect, and thus was chosen for further study. Our data revealed that B5 inhibited the activity of several kinases (such as EGFR, VEGFR2, and PDGFRα) that contributed to the development of non-small cell lung cancer (NSCLC). Besides, an in vivo study also showed that B5 inhibited tumor growth without signs of adverse effects in the A549 xenograft model. In conclusion, B5 may represent a new and promising drug for the treatment of NSCLC.



Publication History

Received: 09 March 2021

Accepted: 08 May 2021

Publication Date:
23 June 2021 (online)

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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