STING agonism has emerged as a promising therapeutic approach for cancer treatment via activation of the host antitumor immune response. Herein, we present a potent STING agonist BSP16 developed based on our STING agonist screening platform. It was demonstrated that BSP16 could effectively bind to STING protein and induce the active conformational transition of STING. In IRF reporter assay, BSP16 strongly activated STING signaling in both human and mouse cells with EC50 = 9.2 μM and 5.7 μM, respectively. The capability of BSP16 to activate STING pathway in vitro was also validated by its regulation of downstream gene transcription and protein expression. In addition, BSP16 had a favorable druggability, including good water solubility, good membrane permeability, good stability, no hERG toxicity, and no CYP3A4 inhibitory activity. In terms of the PK profiles, the exposure of BSP16 in vivo was excellent when administered intravenously and orally and the oral bioavailability of BSP16 was extremely high (F = 107%). Most importantly, BSP16 was proven to be effective in multiple syngeneic models, and in some cases, BSP16 could induce complete tumor regression and durable antitumor immune memory. Moreover, the synergistic antitumor effect of BSP16 combined with anti-PD-L1 therapy in the humanized mouse model of HCC827 lung cancer proved the potential benefits of BSP16 in combination with immune checkpoint inhibitors.
In summary, BSP16 is a promising STING agonist with outstanding in vitro and in vivo activities and favourable druggability, which makes it valuable for further development as a novel anticancer agent.
The development of PARP inhibitors (PARPi) has revolutionized cancer treatment, particularly for BRCA1/2 deficient tumors. However, the emergence of PARPi resistance poses a significant challenge. Our study aimed to explore the mechanisms of this resistance, focusing on the role of DNA end resection.
We induced resistance in the MDA-MB-468 cell line using Talazoparib and Olaparib, creating in vivo models to evaluate drug sensitivity. RNA-seq analysis identified significant gene expression changes in resistant cells, hinting at altered signaling pathways.
Our results showed increased resistance indices and poor drug response in resistant cell lines, confirming resistance development. Establishing over 40 drug-resistant cell lines, our platform is poised to facilitate the advancement of PARP targeted therapies, offering insights into overcoming PARPi resistance in cancer treatment.
The CB1 receptor, a key component of the endocannabinoid system (ECS), is crucial in appetite control, pain perception, mood regulation, obesity, and diabetes. In oncology, the ECS plays a pivotal role in tumors' growth, development, and metastasis, with the activation or inhibition of the CB1 potentially exerting substantial impacts on cancer treatment and prevention. In vitro and in vivo modes are established to understand the signaling pathways of CB1, interactions with other cellular components and the development of more selective novel drugs with fewer side effects. CB1 receptor activation inhibits Forskolin-stimulated adenylate cyclase by G protein (Gαi/o) and increases the phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2) via G protein-dependent and β-arrestin-dependent pathways. Here we constructed an integrated experimental cascade, including in vitro HTRF cAMP assay and β-arretin2 NanoBiT assay, to conduct the high throughput hit-to-lead compound screening, agonist, antagonist and inverse agonist validation. Meanwhile, several CDX modes are constructed for promisingly conducting in-vivo experiments and biomarker detection. Thus, ICE supports multiple approaches for helping the drug discovery and development of CB1 to facilitate the treatment of multiple diseases.
In the specific fields of genetics, epigenetics is the study of heritable changes in gene expression and cell phenotype caused by DNA methylation, histone modification and regulation of non-coding RNA without altering the DNA sequence. Abnormal methylation modification of mRNA and abnormal expression of miRNA and other non-coding RNA often promote the tumorigenesis. Therefore, tumor epigenetic therapy has become an urgent research direction for scholars.
ICE Bioscience has established an epigenetic screening platform for exploration on tumor epigenetic therapy. The platform mainly includes methylation screening platform, acetylation screening platform and mRNA screening platform. It includes about 100 types of epigenetic hot targets, which allows the platform being supportive for preclinical research and anticancer drug validation. Meanwhile, several biochemical and cell-based assays are demonstrated for promisingly conducting in-vitro experiments. Thus, ICE Bioscience epigenetic platform can support tumorigenesis research and new-generation anti-tumor drug development.