Abstract:
:EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR(WT). Finally, the most representative compound 17d was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR(L858R/T790M) over EGFR(WT), which may play an important role in designing new classes of mutant-selective EGFR inhibitors.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Hao Y,Wang X,Zhang T,Sun D,Tong Y,Xu Y,Chen H,Tong L,Zhu L,Zhao Z,Chen Z,Ding J,Xie H,Xu Y,Li Hdoi
10.1021/acs.jmedchem.6b00403subject
Has Abstractpub_date
2016-08-11 00:00:00pages
7111-24issue
15eissn
0022-2623issn
1520-4804journal_volume
59pub_type
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