Sharma Lalit Kumar, Leonardi Roberta, Lin Wenwei, Boyd Vincent A, Goktug Asli, Shelat Anang A, Chen Taosheng, Jackowski Suzanne, Rock Charles O
Department of Chemical Biology and Therapeutics, ‡Department of Infectious Diseases, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.
J Med Chem. 2015 Feb 12;58(3):1563-8. doi: 10.1021/jm501585q. Epub 2015 Jan 21.
Pantothenate kinase (PanK) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. The association of PanK with neurodegeneration and diabetes suggests that chemical modifiers of PanK activity may be useful therapeutics. We performed a high throughput screen of >520000 compounds from the St. Jude compound library and identified new potent PanK inhibitors and activators with chemically tractable scaffolds. The HTS identified PanK inhibitors exemplified by the detailed characterization of a tricyclic compound (7) and a preliminary SAR. Biophysical studies reveal that the PanK inhibitor acts by binding to the ATP-enzyme complex.
泛酸激酶（PanK）是一种控制辅酶A（CoA）生物合成的调节酶。PanK与神经退行性疾病和糖尿病的关联表明，PanK活性的化学调节剂可能是有用的治疗药物。我们对来自圣裘德化合物库的520000多种化合物进行了高通量筛选，确定了具有化学易处理骨架的新型强效PanK抑制剂和激活剂。高通量筛选确定了以三环化合物（7）的详细表征和初步构效关系为例的PanK抑制剂。生物物理研究表明，PanK抑制剂通过与ATP-酶复合物结合发挥作用。
