Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity.
Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity.
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DOI：
10.1021/acs.jmedchem.1c01496
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发表时间：
2021-12-23
影响因子：
7.3
通讯作者：
Ciulli A
中科院分区：
文献类型：
--
作者：
Klein VG;Bond AG;Craigon C;Lokey RS;Ciulli A
用于预测“超越5规则”的蛋白水解靶向嵌合体（PROTAC）降解剂的类药物性质的标准尚不成熟。由于其可靠性，PROTAC组件通常通过酰胺偶联进行组合。然而，酰胺可导致吸收、分布、代谢和排泄（ADME）特性不良。我们假设生物电子等排的酰胺-酯取代可导致物理化学性质和生物活性的改善。使用模型化合物，轴承酰胺或酯，我们确定最佳亲脂性和渗透性的参数。我们应用这些知识设计了一组新型酰胺-酯取代的基于VHL的BET降解剂，目的是增加渗透性。我们的酯PROTAC保持细胞内的稳定性，总体上比其酰胺对应物更有效的降解剂，并显示出更早的钩状效应。这些增强是由更大的细胞渗透性而不是三元复合物形成的改善驱动的。这种在很大程度上未经探索的酰胺-酯取代提供了一种简单的策略来增强PROTAC的渗透性和生物活性，并可能证明对其他Ro 5以外的分子有益。
Criteria for predicting the druglike properties of “beyond Rule of 5” Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules.
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影响因子：
7.3
作者：
Chan KH;Zengerle M;Testa A;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
DOI：
10.1016/j.ddtec.2018.03.001
发表时间：
2018-07-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Caron, Giulia;Vallaro, Maura;Ermondi, Giuseppe
通讯作者：
Ermondi, Giuseppe
影响因子：
7.3
作者：
Bockus, Andrew T.;Schwochert, Joshua A.;Lokey, R. Scott
通讯作者：
Lokey, R. Scott