Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein?Protein Interaction between Menin and Mixed Lineage Leukemia (MLL) [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 620.19 Other engineering materials
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 892-913 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260967
• Chủ đề: 1. 60 applied life sciences; 2. Indoles; 3. Inhibition; 4. Inhibitors; 5. Selectivity; 6. Substituents

Tóm tắt

 Development of potent small molecule inhibitors of protein?protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein?protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with <
 i>
 MLL<
 /i>
  translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound <
 b>
 1<
 /b>
  (MI-136) to identify compounds suitable for in vivo studies in mice. We report this work resulted in the identification of compound <
 b>
 27<
 /b>
  (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over <
 b>
 1<
 /b>
  and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure?activity and structure?property relationships for the menin?MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein?protein interactions for potential therapeutic applications.