Development of EGFR-Tyrosine Kinase Inhibitors Effective for Non-Small Cell Lung Cancer Resistant to Gefitinib

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293028
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Nagasaki University
• Principal Investigator: IWAO Masatomo 長崎大学, 工学研究科, 教授 (00100892)
• Co-Investigator(Kenkyū-buntansha): 石橋 郁人 長崎大学, 水産・環境科学総合研究科(水産), 教授 (10192486) ; 福田 勉 長崎大学, 工学研究科, 助教 (80295097)
• Co-Investigator(Renkei-kenkyūsha): UNNO Hideaki 長崎大学, 工学研究科, 助教 (10452872) ; UEHARA Yoshimasa 岩手医科大学, 薬学部, 教授 (50160213) ; NISHIYA Naoyuki 岩手医科大学, 薬学部, 講師 (10286867)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 非小細胞肺がん / EGFR-TKI / L858R/T790M変異 / L858R/T790M/C797S変異 / ゲフィチニブ耐性 / オシメルチニブ耐性 / ラメラリン / アザラメラリン

Outline of Final Research Achievements

A new class of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) effective against the drug-resistant EGFR mutants has been developed via structural modification of the marine natural product lamellarin N and its lactam congener azalamellain N. Thus, the designed analogues possessing water-solubilizing aminoalkyl group(s) at the A-ring of their pentacyclic lamellarin core exhibited potent inhibitory activity against the gefitinib-resistant EGFR(L858R/T790M) double mutant in enzyme assay. Moreover, these compounds effectively suppressed proliferation of Ba/F3 cells, which were transduced with the osimertinib-resistant EGFR(L858R/T790M/C797S) triple mutant, in EGFR-dependent manner.

Free Research Field

創薬化学