Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.
Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.
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DOI：
10.1016/j.bmc.2020.115877
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发表时间：
2021-01-01
影响因子：
3.5
通讯作者：
Carrick JD
中科院分区：
文献类型：
--
作者：
Downs RP;Xiao Z;Ikedionwu MO;Cleveland JW;Lin Chin A;Cafferty AE;Darryl Quarles L;Carrick JD
遗传性低磷酸盐血症疾病、TIO和CKD疾病被认为受到过量成纤维细胞生长因子-23（FGF-23）的影响，FGF-23激活二元肾FGFR/ α-Klotho复合物以调节磷酸盐和维生素D的稳态代谢。来自具有过量FGF-23的CKD患者的适应性FGF-23应答经常导致心血管疾病的死亡率增加。可逆结合的小分子治疗剂尚未从该领域的研究和开发中出现。本工作中描述的当前成果突出了与使用有机合成的战略类似物来探测结构-活性关系并初步定义从虚拟高通量筛选获得的计算衍生命中的药效团的铅识别和修饰相关的努力。本文报道了用于初始命中和类似物制备的合成策略，以及初步的细胞体外测定结果，其突出了在远低于细胞毒性的浓度下FGF-23信号传导序列的亚微摩尔抑制。
Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area. Current outcomes described in this work highlight efforts related to lead identification and modification using organic synthesis of strategic analogues to probe structure-activity relationships and preliminarily define the pharmacophore of a computationally derived hit obtained from virtual high-throughput screening. Synthetic strategies for the initial hit and analogue preparation, as well as preliminary cellular in vitro assay results highlighting sub micromolar inhibition of the FGF-23 signaling sequence at a concentration well below cytotoxicity are reported herein.
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