Basu Debjit, Richters André, Rauh Daniel
Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
Bioorg Med Chem. 2015 Jun 15;23(12):2767-80. doi: 10.1016/j.bmc.2015.04.038. Epub 2015 Apr 23.
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).
共价激酶抑制剂在治疗表皮生长因子受体（EGFR）依赖性非小细胞肺癌（NSCLC）方面的临床成功，重新唤起了人们对反应性小分子的重视。对一线EGFR抑制剂产生的获得性耐药性仍然是NSCLC治疗的主要瓶颈，目前通过应用微调的共价药物来解决这一问题。在此，我们报告了一类新型的具有共价但可逆弹头的EGFR抑制剂的设计、合成及生化评估。一系列源自苯胺嘧啶和3-取代-2-氰基丙烯酰胺支架的WZ4002类似物，对临床相关的EGFR（L858R）和EGFR（L858R/T790M）表现出强大且选择性的抑制活性。
