Yuki Hitomi, Kikuzato Ko, Koda Yasuko, Mikuni Junko, Tomabechi Yuri, Kukimoto-Niino Mutsuko, Tanaka Akiko, Shirai Fumiyuki, Shirouzu Mikako, Koyama Hiroo, Honma Teruki
Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Drug Discovery Chemistry Platform Unit, RIKEN Center for Life Science Technologies, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Bioorg Med Chem. 2017 Aug 15;25(16):4259-4264. doi: 10.1016/j.bmc.2017.05.053. Epub 2017 Jun 16.
We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond.
我们之前报道了一种基于结构设计的高效造血细胞激酶（HCK）抑制剂，即一种名为RK-20449的吡咯并嘧啶化合物，用于治疗复发性白血病。在此，我们报道了一些7-取代吡咯并嘧啶氨基酸衍生物的合成及构效关系。尽管这些衍生物与RK-20449具有相同的预测结合构象，但其IC值比母体化合物大100至1000倍。我们推测，与HCK的Asp348形成离子键的胺氮的碱性显著影响对HCK的抑制活性。通过从头算量子力学方法预测氮的pKa值，并通过X射线晶体学分析衍生物与HCK的复合物。我们观察到预测的pKa与IC值之间存在显著相关性，且活性较低的衍生物的晶体结构在离子键周围显示出各种类型的缺陷。
