BMS-1001 HCl is an orally active human PD-L1/PD-1 immune checkpoint inhibitor. BMS-1001 HCl exhibits low-toxicity in cells. BMS-1001 binds to human PD-L1 and blocks its interaction with PD-1.
The membrane-bound molecules programmed death 1 (PD-1) and its ligand PD-L1 (PD-1/PD-L1) belong to the immune checkpoint pathway. PD-1 pathway downregulates effector T cells in immune response, thereby causing immune suppression[1]. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade[2]. In a steady state, the interaction of PD-1 with its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) maintains peripheral immune tolerance. However, the expression of PD-L1 on tumor cells and interaction with PD-1 on T cells dampen anti-tumor immunity[3]. PI3K/Akt/mTOR and MAPK signal network induces PD-1/PD-L1 expression and facilitates tumor progression. Transcriptional factors such as hypoxia induced factors, PTEN, p53, CDK5, BRD4, STAT modulate PD-1/PD-L1 expression. PD-1/PD-L1 level is also regulated via epigenetic and post-translational manner[4]. BMS-1001 hydrochloride is an orally active human PD-L1/PD-1 immune checkpoint inhibitor. BMS-1001 hydrochloride exhibits low-toxicity in cells. BMS-1001 binds to human PD-L1 and blocks its interaction with PD-1. BMS-1001 presents low toxicity towards tested cell lines and block the interaction of soluble PD-L1 with the cell surface-expressed PD-1. BMS-1001 alleviates the inhibitory effect of the soluble PD-L1 on the T-cell receptor-mediated activation of T-lymphocytes[5].
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