利用与强效先导化合物结合的 PI3Kα 的 X 射线结构深入了解 PI3K 抑制剂的设计。
New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound.
机构信息
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China.
Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University, School of Medicine, Shanghai, 200025, China.
出版信息
Sci Rep. 2017 Nov 6;7(1):14572. doi: 10.1038/s41598-017-15260-5.
Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α-YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a flexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifically, residue 773(S) in PI3Kα is quite different from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.
磷酸肌醇 3-激酶α 是一个有吸引力的靶点，有望治疗多种癌症。在此，我们描述了一种已报道的 PI3K 抑制剂向具有低分子量的中等 PI3Kα 抑制剂的演变过程。我们使用 X 射线晶体学来描述化合物 YXY-4F 的精确结合模式。p110α-YXY-4F 和 apo p110α 复合物的比较表明，YXY-4F 通过促进 PI3Kα ATP 催化位点残基 Ser773 和 Ser774 的灵活构象变化，诱导了额外的空间。具体而言，PI3Kα 中的残基 773(S)与 PI3Kβ(D)、γ(A)和δ(D)相当不同，这可能指导围绕 NH 基团和苯基的取代基的进一步优化，以提高 PI3Kα 的选择性和效力。
Zotero 插件