کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1370546 981822 2015 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53–MDM2 interaction with a distinct binding mode
کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53–MDM2 interaction with a distinct binding mode
چکیده انگلیسی

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein–protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53–MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53–MDM2 inhibitors.

Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 25, Issue 17, 1 September 2015, Pages 3621–3625
نویسندگان
, , , , , , , , , ,