Charting the Chemical Space of Acrylamide-Based Inhibitors of zDHHC20.
Charting the Chemical Space of Acrylamide-Based Inhibitors of zDHHC20.
复制标题
绘制基于丙烯酰胺的 zDHHC20 抑制剂的化学空间图。
DOI：
10.1021/acsmedchemlett.2c00336
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发表时间：
2022
影响因子：
4.2
通讯作者：
Dickinson,BryanC
中科院分区：
文献类型：
--
作者：
Azizi,Saara-Anne;Delalande,Clémence;Lan,Tong;Qiu,Tian;Dickinson,BryanC
蛋白质s -酰化是一种动态可逆的脂质翻译后修饰，可以影响靶蛋白的活性、稳定性、定位和相互作用。脂质修饰通过硫酯键发生在半胱氨酸残基上，在人类中由23个含Asp-His-His-Cys结构域的蛋白酰基转移酶（DHHC-PATs）介导。dhhc - pat在生理和疾病中具有众所周知的作用，但其生物学功能和治疗潜力仍有待发现。我们最近开发了cyanomyracrylamide (CMA)，这是一种基于丙烯酰胺的DHHC抑制剂，与现有抑制剂相比有了重大改进。本文研究了cmaa及其丙烯酰胺衍生物对zDHHC20的构效关系（SAR）， zDHHC20是人类DHHC家族中结构特征最明显的成员，并对同源zDHHC2进行了验证。该合成孔径图指出了丙烯酰胺支架的局限性和潜力，强调了对二价抑制剂的需求，并通过改进的logP识别了与cma - abt活性相当的三个分子。
Protein S-acylation is a dynamic and reversible lipid post-translational modification that can affect the activity, stability, localization, and interactions of target proteins. Lipid modification occurs on cysteine residues via a thioester bond and in humans is mediated by 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). The DHHC-PATs have well-known roles in physiology and disease, but much remains to be discovered about their biological function and therapeutic potential. We recently developed cyanomyracrylamide (CMA), an acrylamide-based DHHC inhibitor with key improvements over existing inhibitors. Here we conduct a structure–activity relationship (SAR) study ofCMAand its acrylamide derivatives against zDHHC20, the most structurally characterized member of the human DHHC family, and validate the results against the homologous zDHHC2. This SAR maps out the limitations and potential of the acrylamide scaffold, underscoring the need for a bivalent inhibitor and identifying along the way three molecules with activity on par withCMAbut with an improved logP.