DeYoung Emma G, Howe Justin M, Fang Siteng, Reddy Mullapudi Mohan, Handel Jillian P, Gillen Miller Jared T, Wheeler Daniel R, Tumey L Nathan
Binghamton University School of Pharmacy and Pharmaceutical Sciences, Johnson City, New York 13790, United States.
ACS Med Chem Lett. 2023 Sep 14;14(10):1358-1368. doi: 10.1021/acsmedchemlett.3c00260. eCollection 2023 Oct 12.
TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist that could be delivered by antibody-drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure-activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts. We found that the addition of hydrophobic acyl tails to parent compound generally resulted in retained or improved TLR7 agonist activity without sacrificing the permeability or the selectivity over TLR8. In contrast, the addition of a simple alkyl tail at the same position resulted in a dramatic loss in potency. Molecular modeling was performed to provide a rationale for this dramatic loss in potency. We ultimately identified compounds , , and as highly potent TLR7 agonists that potently induced the activation of mouse macrophages and hPBMCs at low-nanomolar concentrations.
Toll样受体7（TLR7）激动剂在多种肿瘤学和自身免疫应用中具有显著的治疗潜力。我们最近报道了一种强效的TLR7选择性激动剂，它可以通过抗体-药物偶联物（ADC）技术递送，以引发强效的抗癌活性。在此，我们报告了合成化学和构效关系研究，以开发用于下一代ADC研究的具有更高效力的TLR7激动剂。我们发现，在母体化合物上添加疏水酰基尾通常会导致TLR7激动剂活性得以保留或提高，而不会牺牲其通透性或对TLR8的选择性。相比之下，在相同位置添加一个简单的烷基尾会导致效力急剧丧失。进行了分子建模，以解释这种效力急剧丧失的原因。我们最终确定化合物、和为高效的TLR7激动剂，它们在低纳摩尔浓度下能有效诱导小鼠巨噬细胞和人外周血单个核细胞（hPBMC）的激活。
