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基于AG-946的结构设计,它是一种酸盐激酶激活剂

Tao Liu¹, Anil K Padyana², Evan T Judd³

¹Ensem Therapeutics, 880 Winter St, Waltham, MA 02451, USA.

|December 18, 2023

概括

研究人员设计了AG-946,它是酸盐激酶 (PK) 和其红细胞形式 (PKR) 的强有力的激活剂. 这种小分子因其在治疗PK相关疾病方面的潜力而进入临床试验.

科学领域:

生物化学生物化学
酶学是一种酶学.
药物发现药物发现药物发现

背景情况:

酸盐激酶 (PK) 是一个关键的糖解酶,调节细胞代谢.
PKR是PK的红细胞特异性异型.
基因酶活性的失调与各种代谢障碍有关.

研究的目的:

描述AG-946的基于结构的设计,AG-946是一种PK异型的新型全激活剂.
与以前的支架相比,提高对PKR的效力和选择性.
评估AG-946在激活野生类型和突变PK酶中的有效性.

主要方法:

基于结构的药物设计,使用伪C2对称原则.
生物化学试验以确定激活功率 (AC50) 和动力学.
在变质条件下进行酶稳定性测试.

主要成果:

AG-946证明了野生类型PK (AC50 = 0.005 μM) 和突变K410E (AC50 = 0.0043 μM) 和R510Q (AC50 = 0.0069 μM) 的强烈激活.
与参考化合物相比,AG-946的激活半衰期显著长 (>150倍).
在变化条件下,AG-946稳定了不稳定的PKR R510Q突变体的催化活性.

结论:

AG-946是一种强效的,可口服的,小分子性激活剂,用于野生型和突变型PKR.
药物的设计改善了功效,并减少了目标外活动.
AG-946已被推进到人类临床试验,以寻找潜在的治疗应用.

关键词:

AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 AG-946 全osterism 的意思是说,所有osterism 的意思是说,所有的osterism.医学化学医学化学药物动力学药物动力学酸盐酶激活剂激活剂

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