Scholarlink

<p>Developing small-molecule compounds as effective and safe pharmaceuticals relies on their ability to bind disease-associated proteins with high affinity and selectivity. However, achieving ultra-high affinity in the femtomolar range is a major challenge in medicinal chemistry due to the inherent constraints of protein-ligand interactions. Here, we introduce a novel class of di-meta-substituted fluorinated benzenesulfonamide compounds that achieve an extraordinary dissociation constant of 44 fM for carbonic anhydrase IX (CAIX). CAIX, a transmembrane enzyme implicated in hypoxic tumor progression through the increase of microenvironment acidity, represents a promising target for anticancer therapy. Inhibiting CAIX may help suppress tumor growth and improve cancer treatment outcomes. The newly developed compounds exhibit the highest affinity for CAIX reported to date and rank among the strongest known non-covalent small-molecule inhibitors.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Achieving femtomolar affinities in structure-based drug design

  • 期刊论文

  • 发表日期：

    2026年1月19日

查看全文
  • Asta Zubrienė,
  • Maija Kurtenoka,
  • Vaida Paketurytė-Latvė,
  • Janis Leitans,
  • Elena Manakova,
  • Mantas Žvirblis,
  • Andris Kazaks,
  • Vladislava Eimonta,
  • Kaspars Tars,
  • Saulius Gražulis,
  • Vytautas Petrauskas,
  • Jurgita Matulienė,
  • Virginija Dudutienė,
  • Kirill Shubin,
  • Daumantas Matulis

摘要

Developing small-molecule compounds as effective and safe pharmaceuticals relies on their ability to bind disease-associated proteins with high affinity and selectivity. However, achieving ultra-high affinity in the femtomolar range is a major challenge in medicinal chemistry due to the inherent constraints of protein-ligand interactions. Here, we introduce a novel class of di-meta-substituted fluorinated benzenesulfonamide compounds that achieve an extraordinary dissociation constant of 44 fM for carbonic anhydrase IX (CAIX). CAIX, a transmembrane enzyme implicated in hypoxic tumor progression through the increase of microenvironment acidity, represents a promising target for anticancer therapy. Inhibiting CAIX may help suppress tumor growth and improve cancer treatment outcomes. The newly developed compounds exhibit the highest affinity for CAIX reported to date and rank among the strongest known non-covalent small-molecule inhibitors.