Roman Jeff, Yuan Yue, Xu Yue, Zhu Qiusha, Wu Shaowen, Zhao Fang, Zhou Xue, Meng Shi, Han Dongna, Sharp Kim, Chen Li, Li Changhong, Doliba Nicolai M
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Nanjing AscendRare Pharmaceutical Technology, Nanjing, China.
Diabetes. 2025 Aug 1;74(8):1374-1384. doi: 10.2337/db25-0066.
Glucokinase (GK) activators (GKAs) are a long-sought therapeutic modality for the treatment of type 2 diabetes. However, GKAs have failed in clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with those of the unsuccessful GKA MK-0941 (Merck Pharmaceuticals), which is well characterized both clinically and mechanistically. Dorzagliatin improved glucose-stimulated insulin secretion in a dose- and glucose-dependent manner, in contrast to MK-0941, which induced maximal insulin secretion at low doses and glucose concentrations. To understand these functional differences, the atomic resolution structure of the dorzagliatin-GK complex was determined and compared with the GK-MK-0941 structure. MK-0941 bound to a pocket accessible in both open and closed conformations; had a strong interaction with Y214, the mutation of which produces the most clinically severe activating mutation; and produced a high energy barrier for the open-to-closed transition. In contrast, dorzagliatin only bound favorably to the closed form of GK, interacting primarily with R63 and causing a low energy barrier for the open-to-closed transition. This provides the molecular rationale for the clinical success of dorzagliatin, which can guide the future development of next-generation allosteric activators of GK.
The type 2 diabetes (T2D) treatment dorzagliatin has achieved singular success among its drug class, known as glucokinase (GK) activators (GKAs). A comprehensive approach using human islet perifusions, enzyme kinetics, X-ray crystallography, and modeling studies revealed the unique mechanism by which dorzagliatin activates GK. Dorzagliatin dose-dependently reduces the glucose threshold for stimulation of insulin secretion and binds preferably to the closed form of GK, preventing overstimulation of the enzyme. A renewed interest in GKAs, coupled with modern tools to assess their molecular interactions with GK, should guide the future development of novel GKA treatments for T2D.
葡萄糖激酶（GK）激活剂（GKAs）是治疗2型糖尿病长期以来寻求的一种治疗方式。然而，除了最近的多扎格列艾汀（华领医药）外，GKAs在临床试验中均告失败。本研究采用人胰岛灌注、酶动力学、X射线晶体学和建模研究等综合方法，比较多扎格列艾汀与未成功的GK激活剂MK-0941（默克制药）的作用效果，MK-0941在临床和机制方面都有充分的特征描述。与MK-0941不同，多扎格列艾汀以剂量和葡萄糖依赖的方式改善葡萄糖刺激的胰岛素分泌，MK-0941在低剂量和葡萄糖浓度下诱导最大胰岛素分泌。为了解这些功能差异，确定了多扎格列艾汀-GK复合物的原子分辨率结构，并与GK-MK-0941结构进行比较。MK-0941结合在开放和封闭构象均可进入的口袋中；与Y214有强烈相互作用，Y214的突变产生临床上最严重的激活突变；并为开放到封闭的转变产生高能量屏障。相比之下，多扎格列艾汀仅与GK的封闭形式有良好结合，主要与R63相互作用，并为开放到封闭的转变产生低能量屏障。这为多扎格列艾汀的临床成功提供了分子理论依据，可指导GK下一代变构激活剂的未来开发。
2型糖尿病（T2D）治疗药物多扎格列艾汀在其所属药物类别即葡萄糖激酶（GK）激活剂（GKAs）中取得了独特的成功。采用人胰岛灌注、酶动力学、X射线晶体学和建模研究等综合方法揭示了多扎格列艾汀激活GK的独特机制。多扎格列艾汀以剂量依赖的方式降低刺激胰岛素分泌的葡萄糖阈值，并优先结合GK的封闭形式，防止酶的过度刺激。对GKAs的重新关注，以及评估它们与GK分子相互作用的现代工具，应能指导T2D新型GKA治疗药物的未来开发。
