BMS-202 is a nonpeptidic PD-1/PD-L1 complex inhibitor binding to PD-L1 and blocks human PD-1/PD-L1 interaction (IC50=53.6nM) to prevent cancer cells from escaping antitumor immune responses[1,2]. The binding of the PD-L1 molecule in the BMS-202/PD-L1 complexes is similar to the binding of the anti-PD-L1 nanobody KN035 and VH domain of avelumab at N-terminal loop in PD-1, occluding the PD-1 interaction surface of PD-L1s[3].
In vitro experiments show that BMS-202 inhibits cell malignancy in human glioblastoma (10μM; 48h)[4]. BMS-202 also suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway in a mouse pituitary Lβt2 cell model (20μM; 24h)[5]. BMS-202 may act as an inhibitor of programmed cell death ligand (0.1µM, 1µM, 10µM, 100 µM, and 500µM; 48h) in HaCaT immortalized human keratinocytes[6].
In vivo experiments show that BMS-202 performs an anti-tumor effect in the humanized MHC-double knockout NOG mouse (20mg/kg; 9 times; i.v)[7]. BMS-202 also significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin (8mM, 200ul; topically introduction on skin)[8].
References:
[1] Liu, Jin et al. “Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents.” *Journal of medicinal chemistry* vol. 66,18 (2023): 13172-13188. doi:10.1021/acs.jmedchem.3c01141
[2] Bailly, Christian, and Gérard Vergoten. “Flurbiprofen as a biphenyl scaffold for the design of small molecules binding to PD-L1 protein dimer.” *Biochemical pharmacology* vol. 178 (2020): 114042. doi:10.1016/j.bcp.2020.114042
[3] Zak, Krzysztof M et al. “Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2.” *Structure (London, England : 1993)*vol. 25,8 (2017): 1163-1174. doi:10.1016/j.str.2017.06.011
[4] Yang, Xueou et al. “Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma.” *Cell death & disease* vol. 15,3 186. 4 Mar. 2024, doi:10.1038/s41419-024-06553-5
[5] Jiang, Ying et al. “The PD-1/PD-L1 binding inhibitor BMS-202 suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway.” *Drug development research* vol. 83,1 (2022): 176-183. doi:10.1002/ddr.21857
[6] Shafi, Hasham et al. “Comprehensive Advanced Physicochemical Characterization and In Vitro Human Cell Culture Assessment of BMS-202: A Novel Inhibitor of Programmed Cell Death Ligand.” *Pharmaceutics* vol. 16,11 1409. 1 Nov. 2024, doi:10.3390/pharmaceutics16111409
[7] Ashizawa, Tadashi et al. “Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse.” *Biomedical research (Tokyo, Japan)* vol. 40,6 (2019): 243-250. doi:10.2220/biomedres.40.243
[8]Dickinson, Sally E et al. “Inhibition of UV-Induced Stress Signaling and Inflammatory Responses in SKH-1 Mouse Skin by Topical Small-Molecule PD-L1 Blockade.” *JID innovations : skin science from molecules to population health* vol. 4,2 100255. 5 Jan. 2024, doi:10.1016/j.xjidi.2023.100255
BMS-202是一种非肽性PD-1/PD-L1复合物抑制剂，与PD-L1隔离PD-1/PD-L1二聚体形成（IC50=53.6nM），以结合阻断人PD-1/PD-L1相互作用，从而抑制免疫反应抑制，从而阻止癌细胞逃避抗肿瘤免疫反应[1,2]。PD-L1分子在BMS-202/PD-L1复合物中的结合类似于抗PD-L1纳米体KN035与avelumab在PD-1 n端环上的VH结构域的结合，阻断PD-L1的与PD-1的相互作用表面[3]。
体外实验表明，BMS-202对人胶质母细胞瘤（10μM; 48h）细胞恶性肿瘤有抑制作用[4]。在小鼠垂体l - βt2细胞模型（20μM; 24h）中，BMS-202还能抑制促性腺激素的合成和分泌，并通过p38 MAPK信号通路促进细胞凋亡[5]。BMS-202在HaCaT永活的人角质形成细胞中作为程序性细胞死亡配体的抑制剂（0.1µM, 1µM, 10µM, 100µM和500µM; 48h）[6]。
体内实验表明，BMS-202在人源化mhc双敲除NOG小鼠模型中具有抗肿瘤作用 (20mg/kg; 9次; 静脉注射）[7]。BMS-202还显著降低了SKH-1生物发光报告小鼠皮肤（8mM; 200ul; 局部皮肤涂抹）中紫外线诱导的激活蛋白-1转录活性[8]。