Chopra Chirag, Yodun Tenzen, Singh Harpreet, Singh Bhupender, Singh Shashank K, Goutam Umesh
School of Bioengineering and Biosciences, Lovely Professional University Phagwara, Punjab, India.
Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR) Jammu, J&K, India.
Am J Transl Res. 2023 Aug 15;15(8):5206-5215. eCollection 2023.
Immunotherapeutic interventions in cancer have been considerably successful and widely accepted for cancer treatment, but are costly and cannot be afforded by all patients. Because of the high cost, the pharmaceutical research groups across the world are sufficiently motivated to discover or design small molecule inhibitors to treat cancer through inhibition of the immune checkpoint proteins previously targeted with monoclonal antibodies. The presented study was designed with an aim to establish raloxifene, a selective estrogen receptor modulator (SERM) as a potential ligand of the immune checkpoint protein Programmed death ligand-1 (PD-L1).
In the presented study, the approach was used for identifying a lead molecule against PD-L1. The hits were screened using the similarity-search method, and drug-likeliness analysis, and the leads were identified through ligand-docking using Autodock. In-vitro cytotoxicity analysis was carried out using the standard sulphorhodamine B (SRB) assay and the wound healing analysis to show the inhibition of cellular migration was performed using the standard scratch assay.
The study revealed that raloxifene showed a high drug likelihood and higher binding affinity with PD-L1 as compared to the positive control (; BMS is Bristol Myers Squibb). The binding of raloxifene was shown to occur in the same region as the FDA-approved monoclonal antibodies atezolizumab and durvalumab, indicating the potential of raloxifene for PD1/PD-L1 blockade. In the studies, raloxifene showed a time-dependent reduction in IC values for the cell line HCT116 (colon cancer). The scratch assay also revealed that raloxifene significantly reduced the migratory potential of HCT-116 cells in-vitro.
PD-L1 is a potential target of the SERM raloxifene in-silico. Overall, this study is one step further towards immune checkpoint blockade using small-molecule inhibitors.
癌症免疫治疗干预已取得相当大的成功并被广泛用于癌症治疗，但成本高昂，并非所有患者都能负担得起。由于成本高昂，全球的制药研究团队都有足够的动力去发现或设计小分子抑制剂，通过抑制先前用单克隆抗体靶向的免疫检查点蛋白来治疗癌症。本研究旨在确定雷洛昔芬，一种选择性雌激素受体调节剂（SERM），作为免疫检查点蛋白程序性死亡配体-1（PD-L1）的潜在配体。
在本研究中，采用该方法来鉴定针对PD-L1的先导分子。通过相似性搜索方法和药物类药性分析对命中物进行筛选，并使用Autodock通过配体对接来鉴定先导物。使用标准的磺酰罗丹明B（SRB）测定法进行体外细胞毒性分析，并使用标准划痕试验进行伤口愈合分析以显示细胞迁移的抑制情况。
该研究表明，与阳性对照（；BMS是百时美施贵宝公司）相比，雷洛昔芬具有较高的药物类药性且与PD-L1具有更高的结合亲和力。雷洛昔芬的结合显示发生在与FDA批准的单克隆抗体阿特珠单抗和度伐鲁单抗相同的区域，表明雷洛昔芬具有PD1/PD-L1阻断的潜力。在研究中，雷洛昔芬显示出对HCT-116细胞系（结肠癌）的IC值呈时间依赖性降低。划痕试验还表明，雷洛昔芬在体外显著降低了HCT-116细胞的迁移潜力。
在计算机模拟中，PD-L1是SERM雷洛昔芬的潜在靶点。总体而言，本研究朝着使用小分子抑制剂进行免疫检查点阻断又迈进了一步。
