PD-1-IN-1 (CA-170) is an orally active dual inhibitor of the immune checkpoint regulatory proteins VISTA and PD-L1[1]. PD-1-IN-1 (CA-170) does not directly bind to the target proteins; its mechanism of action might involve blocking their downstream signaling pathways[2]. PD-1-IN-1 (CA-170) exhibits anti-tumor activity similar to that of PD-1 monoclonal antibodies and offers advantages in terms of biosafety[3].
In vitro, PD-1-IN-1 (CA-170) (10-1000nM) treatment of human peripheral blood mononuclear cells (PBMCs) for 48h did not induce the secretion of cytokines IL-2, IFN-γ, and TNF-α, while anti-CD28 antibodies could induce this secretion [4].
In vivo, oral administration of PD-1-IN-1 (CA-170) (10 mg/kg) for 14 days inhibited tumor growth in a mouse model of colon cancer by 36%. However, it did not show significant efficacy in severely immunocompromised mice, demonstrating that the efficacy of PD-1-IN-1 (CA-170) relies on an immune-mediated mechanism[4]. In a mouse model of lung cancer, oral administration of PD-1-IN-1 (CA-170) (10 mg/kg) for 28 days reduced tumor burden by 63%, increased the number of intratumoral CD8+ T cells, and inhibited lung cancer metastasis[5].
References:
[1]Lazorchak A S, Patterson T, Ding Y, et al. Abstract A36: CA-170, an oral small molecule PD-L1 and VISTA immune checkpoint antagonist, promotes T cell immune activation and inhibits tumor growth in pre-clinical models of cancer[J]. Cancer Immunology Research, 2017, 5: A36-A36.
[2]Musielak B, Kocik J, Skalniak L, et al. CA-170–a potent small-molecule PD-L1 inhibitor or not?[J]. Molecules, 2019, 24(15): 2804.
[3]Wu Q, Jiang L, Li S, et al. Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway[J]. Acta Pharmacologica Sinica, 2021, 42(1): 1-9.
[4]Sasikumar P G, Sudarshan N S, Adurthi S, et al. PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy[J]. Communications biology, 2021, 4(1): 699.
[5]Pan J, Chen Y, Zhang Q, et al. Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA[J]. Communications biology, 2021, 4(1): 906.
PD-1-IN-1 (CA-170) 是一种具有口服活性的免疫检查点调节蛋白VISTA和PD-L1双重抑制剂[1]。 PD-1-IN-1 (CA-170) 不与靶点蛋白直接结合，作用机制可能是阻断它们的下游信号通路[2]。PD-1-IN-1 (CA-170) 表现出与PD-1单克隆抗体相似的抗肿瘤活性，且在生物安全性方面更具优势[3]。
在体外，PD-1-IN-1 (CA-170)（10-1000nM）处理人外周血单核细胞（PBMCs）48h，不诱导细胞因子IL-2、IFN-γ和TNF-α的分泌，而抗CD28抗体可以诱导[4]。
在体内，PD-1-IN-1 (CA-170)（10 mg/kg）通过口服治疗结肠癌小鼠14天，对肿瘤生长抑制率为36%，但对严重免疫缺陷的小鼠没有显著疗效，证明了PD-1-IN-1 (CA-170)的功效需要免疫介导机制[4]。PD-1-IN-1 (CA-170)（10 mg/kg）通过口服治疗肺癌小鼠28天，使肿瘤负荷降低了63%，促进了肿瘤内CD8+ T细胞的增加，抑制了肺癌的转移[5]。