变构调节
丙酮酸激酶
激活剂(遗传学)
糖酵解
巴基斯坦卢比
激酶
生物化学
化学
酶激活剂
酶
蛋白激酶R
蛋白激酶A
受体
细胞周期蛋白依赖激酶2
作者
Tao Liu,Anil K. Padyana,Evan T. Judd,Lei Jin,Dalia I. Hammoudeh,Charles Kung,Lenny Dang
标识
DOI:10.1002/cmdc.202300559
摘要
Pyruvate kinase (PK) is the enzyme that catalyzes the conversion of phosphoenolpyruvate and adenosine diphosphate to pyruvate and adenosine triphosphate in glycolysis and plays a crucial role in regulating cell metabolism. We describe the structure-based design of AG-946, an activator of PK isoforms, including red blood cell-specific forms of PK (PKR). This was designed to have a pseudo-C2-symmetry matching its allosteric binding site on the PK enzyme, which increased its potency toward PKR while reducing activity against off-targets observed from the original scaffold. AG-946 (1) demonstrated activation of human wild-type PK (half-maximal activation concentration [AC50 ]=0.005 μM) and a panel of mutated PK proteins (K410E [AC50 =0.0043 μM] and R510Q [AC50 =0.0069 μM]), (2) displayed a significantly longer half-time of activation (>150-fold) compared with 6-(3-methoxybenzyl)-4-methyl-2-(methylsulfinyl)-4,6-dihydro-5H-thieno[2',3':4,5]pyrrolo[2,3-d]pyridazin-5-one, and (3) stabilized PKR R510Q, an unstable mutant PKR enzyme, and preserved its catalytic activity under increasingly denaturing conditions. As a potent, oral, small-molecule allosteric activator of wild-type and mutant PKR, AG-946 was advanced to human clinical trials.
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