Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.
Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Department of Oncology, Wayne State University School of Medicine, 421 East Canfield Street, Detroit, MI 48201, United States.
J Mol Graph Model. 2018 May;81:125-133. doi: 10.1016/j.jmgm.2018.02.007. Epub 2018 Feb 20.
All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics. Four-point validated models (pharmacophores) were generated for PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA) based on inhibition (IC) of proliferation of isogenic Chinese hamster ovary (CHO) cells engineered to express only human PCFT or only RFC. Our results revealed substantial differences in structural features required for transport of novel molecules by these transporters which can be utilized for developing transporter-selective antifolates.
所有临床使用的抗叶酸缺乏对肿瘤与正常细胞的转运选择性，导致剂量限制毒性。人们越来越感兴趣的是开发新型的肿瘤靶向细胞毒性抗叶酸，通过质子偶联叶酸转运体（PCFT）选择性地转运到肿瘤中，而不是普遍表达的还原叶酸载体（RFC）。缺乏 X 射线晶体结构或预测模型的 PCFT 或 RFC 阻碍了基于结构的药物设计，以获得对 PCFT 具有选择性的治疗药物。基于对仅表达人 PCFT 或仅表达 RFC 的同源中国仓鼠卵巢（CHO）细胞增殖抑制（IC），为 PCFT/活性（HBA、NI、RA、RA）和 RFC/活性（HBD、NI、HBA、HBA）生成了四点验证模型（药效团）。我们的结果揭示了这些转运体转运新型分子所需的结构特征有很大的差异，可用于开发转运体选择性的抗叶酸。
