Discovery of pteridin-7(8H)-one-based irreversible inhibitors targeting the epidermal growth factor receptor (EGFR) kinase T790M/L858R mutant.
The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.
Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology , Shanghai 200237, China.
Wei
W
Zhou
Xiaofeng
X
Liu
Zhengchao
Z
Tu
Lianwen
L
Zhang
Xin
X
Ku
Fang
F
Bai
Zhenjiang
Z
Zhao
Yufang
Y
Xu
Ke
K
Ding
Honglin
H
Li
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011621:Pteridines / Q000737:chemistry*; D011799:Quinazolines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D011621:Pteridines; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib