PD-1-IN-1 (CA-170) (Synonyms: CA-170)

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.