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Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR.

Abstract：

:The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFR(L858R) and EGFR(L858R/T790M).

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Basu D,Richters A,Rauh D

doi

10.1016/j.bmc.2015.04.038

subject

Has Abstract

pub_date

2015-06-15 00:00:00

pages

2767-80

issue

12

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)00344-2

journal_volume

23

pub_type

杂志文章

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