Eisai Inc., 35 Cambridgepark Drive, Cambridge, MA 02140, USA.
H3 Biomedicine, 300 Technology Square FL5, Cambridge, MA 02139, USA.
ChemMedChem. 2021 Jun 7;16(11):1740-1743. doi: 10.1002/cmdc.202100068. Epub 2021 Feb 25.
A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.
一种强效且广谱的干扰素基因刺激物（STING）激动剂的设计策略。通过在核苷酸碱基之间引入一个跨环的大环桥，将环状二核苷酸的生物活性 U 型构象锁定，从而得到一种拓扑新颖的大环桥联 STING 激动剂（MBSA）。除了显著增强的效力外，新设计的 MBSA，以临床候选药物 E7766 为例，在所有主要的人类 STING 变体中均表现出广谱的全基因型活性。在小鼠肝转移瘤模型中，E7766 表现出强大的抗肿瘤活性和持久的免疫记忆反应。还描述了两种互补的对映选择性合成 E7766 的路线。
