Barnwal Anjali, Das Sanjeev, Bhattacharyya Jayanta
Centre for Biomedical Engineering, Indian Institute of Technology, Delhi110016, India.
Department of Biomedical Engineering, All India Institute of Medical Science, Delhi110029, India.
ACS Pharmacol Transl Sci. 2023 Jan 12;6(2):281-289. doi: 10.1021/acsptsci.2c00214. eCollection 2023 Feb 10.
Cancer treatment by inhibiting the PD-1/PD-L1 pathway using monoclonal antibodies has made great advances as it showed long-lasting antitumor responses in a wide range of cancers. However, antibodies exhibit several disadvantages, which include low permeability, immune-related adverse effects, complex synthetic procedures, and high treatment costs. Hence, small-molecule inhibitors can be used as alternatives; however, no small molecule with activity has been reported. In addition, there are many challenges in developing a new drug, including the timeline and escalating cost. Therefore, repurposing an approved drug offers advantages over the development of an entirely new drug. Herein, we identify an FDA-approved small-molecule drug, Ponatinib, as a PD-L1 inhibitor via virtual drug screening of the ZINC database. Ponatinib showed stable binding with PD-L1, with the highest binding energy among all of the screened FDA-approved drugs. The binding of Ponatinib with PD-L1 was supported by a fluorescence quenching assay and immunofluorescence study. Further, we compared the antitumor efficacy of Ponatinib with a commercially available anti-PD-L1 antibody in the murine melanoma model. Ponatinib was found to be more efficient in delaying tumor growth than the anti-PD-L1 antibody. Furthermore, Ponatinib also reduced the expression of PD-L1 in tumors and increased the T-cell population. Interestingly, splenocytes isolated from Ponatinib-treated mice showed enhanced cytotoxic T-cell (CTL) activity against B16-F10 cells. However, Ponatinib itself did not have any direct toxic effect on cancer cells . These findings suggest that Ponatinib can be used as a potent small-molecule inhibitor of PD-L1 to overcome the disadvantages associated with antibodies.
通过使用单克隆抗体抑制PD-1/PD-L1通路进行癌症治疗已经取得了巨大进展，因为它在多种癌症中显示出持久的抗肿瘤反应。然而，抗体存在几个缺点，包括渗透性低、免疫相关不良反应、合成程序复杂以及治疗成本高。因此，小分子抑制剂可以作为替代物；然而，尚未有具有活性的小分子被报道。此外，开发一种新药存在许多挑战，包括时间线和成本不断上升。因此，重新利用已批准的药物比开发全新的药物具有优势。在此，我们通过对ZINC数据库进行虚拟药物筛选，确定一种FDA批准的小分子药物波纳替尼为PD-L1抑制剂。波纳替尼与PD-L1表现出稳定的结合，在所有筛选的FDA批准药物中具有最高的结合能。波纳替尼与PD-L1的结合得到了荧光猝灭试验和免疫荧光研究的支持。此外，我们在小鼠黑色素瘤模型中比较了波纳替尼与市售抗PD-L1抗体的抗肿瘤疗效。发现波纳替尼在延缓肿瘤生长方面比抗PD-L1抗体更有效。此外，波纳替尼还降低了肿瘤中PD-L1的表达并增加了T细胞群体。有趣的是，从接受波纳替尼治疗的小鼠中分离出的脾细胞对B16-F10细胞显示出增强的细胞毒性T细胞（CTL）活性。然而，波纳替尼本身对癌细胞没有任何直接毒性作用。这些发现表明，波纳替尼可以用作一种有效的PD-L1小分子抑制剂，以克服与抗体相关的缺点。
