Vaškevičius Aivaras, Trumpickaitė Gabrielė, Parafjanovič Edvin, Manakova Elena, Mickevičiūtė Aurelija, Gedgaudas Marius, Kojis Tautvydas, Paketurytė-Latvė Vaida, Smirnov Alexey, Baranauskiene Lina, Gražulis Saulius, Zubrienė Asta, Dudutienė Virginija, Matulis Daumantas
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, LT-10257, Lithuania.
Department of Protein - DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, 10257, Vilnius, Lithuania.
Chemistry. 2025 Mar 25;31(18):e202404409. doi: 10.1002/chem.202404409. Epub 2025 Feb 17.
High affinity and selectivity for intended targets is an important goal of small molecule design in drug discovery, yet balancing molecular flexibility and rigidity remains a challenge. While flexible compounds can increase target affinity, they often result in non-specific interactions and reduced selectivity. In contrast, rigid compounds may recognize their target more precisely and have lower off-target effects. In this study, we incorporated a 1,1-dioxido-1,4-thiazine ring into fluorinated benzenesulfonamide derivatives with bulky meta-substituents to enhance selectivity for human carbonic anhydrase IX (CAIX), an important cancer-associated target. Due to the structural similarities of CAIX with other carbonic anhydrase isozymes, selective inhibition remains a significant challenge. A series of 3,4-substituted trifluorobenzenesulfonamides containing oxidized thiazine rings were synthesized using a novel synthetic pathway. Although the potency against CAIX was modestly reduced compared to more flexible analogs, selectivity increased significantly, with lead compounds 7 d and 7 e exhibiting over 1000-fold selectivity for CAIX over most other isozymes. X-ray crystallography revealed the structural basis for this selectivity, confirming the advantageous positioning of rigidified compounds within some CA isozyme active sites. These findings highlight the potential of molecular rigidity in the design of highly selective inhibitors for therapeutic applications.
对预期靶点具有高亲和力和选择性是药物研发中小分子设计的一个重要目标，但平衡分子的灵活性和刚性仍然是一项挑战。虽然柔性化合物可以增加靶点亲和力，但它们往往会导致非特异性相互作用并降低选择性。相比之下，刚性化合物可能更精确地识别其靶点，并且脱靶效应较低。在本研究中，我们将1,1-二氧化-1,4-噻嗪环引入到带有庞大间位取代基的氟化苯磺酰胺衍生物中，以提高对人碳酸酐酶IX（CAIX）的选择性，CAIX是一个重要的癌症相关靶点。由于CAIX与其他碳酸酐酶同工酶在结构上相似，选择性抑制仍然是一个重大挑战。我们使用一种新颖的合成途径合成了一系列含有氧化噻嗪环的3,4-取代三氟苯磺酰胺。尽管与更具柔性的类似物相比，对CAIX的活性略有降低，但选择性显著提高，先导化合物7d和7e对CAIX的选择性比对大多数其他同工酶高出1000倍以上。X射线晶体学揭示了这种选择性的结构基础，证实了刚性化化合物在某些CA同工酶活性位点内的有利定位。这些发现突出了分子刚性在设计用于治疗应用的高选择性抑制剂方面的潜力。
