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Microsatellite Instability (MSI) is a condition characterized by the presence of mutations in microsatellite regions of DNA, which can lead to the accumulation of mutations in these re- gions and result in genomic instability. This phenomenon occurs in various cancer types. Werner helicase (WRN) plays a crucial role in highly MSI (MSI-H) cancer cells, causing syn- thetic lethality when WRN is inhibited or knocked out. Previous studies have revealed that WRN inhibitors, such as HRO761 and VVD-214, can effectively kill MSI-H cancer cells, includ- ing human colorectal cell lines HCT116 and SW48.

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Molecular glue degraders (MGDs) promote the proximity of target proteins to E3 ubiquitin ligases, enabling degrada­tion of previously "undruggable" proteins. VAV1-targeting MGDs, like MRT6160, show promise in treating immuno­logical diseases by reducing inflammation and autoimmune responses. Our integrated platform uses advanced in vitro assays to explore these MGDs, including complex detection, intracellular protein interaction analysis, and deg­radation studies. It also evaluates T and B cell activities and cytokine profiles. By addressing challenges such as complex formation and selectivity, our platform provides a universal solution for discovering and optimizing MGDs with broad therapeutic potential.

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Covalent inhibitors have emerged as indispensable components in drug discov- ery and therapeutic development, with the irreversible nature of those target en- gagement positioning liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) as a powerful approach for high-throughput screening of these molecular entities.

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Prostate cancer (PCa) is common and mostly androgen dependent cancer occurred in men and ranked fifth of the causes of death over the world, reduction the serum level of androgen become the priority therapy method for treat­ing PCa patients. Although the first generation of anti-androgen receptor (AR) new drugs such as flutamide, nilut­amide, and bicalutamide were launched few years ago and lighted new hopes for treatment of androgen dependent PCa, drug resistance was developed quickly and push the second generation of anti-AR drugs such as enzalutamide, apalutamide, and darolutamide to the market by their high specific binding to AR and better drug efficacy. Despite new anti-AR drugs exerted better efficacy, drug resistance still hampered the treatment of PCa patients, new chal­lenge was burst for anti-PCa drugs through AR pathway. In this study, we developed an enzalutamide resistant C4-2B cell line in vitro by escalated the enzalutamide concentration gradually. The phenotype and genotype of C4-2B cell line were checked while enzalutamide concentration was increased. After 6 months of induction and identification, C4-2B enzalutamide resistant cell line was established and showed 140 times of drug-resistant index compare to that of parental cell. The in vivo drug-resistant efficacy was also confirmed in C4-2B enzalutamide resistant (C4-2B Enz-R) CDX models using 30 mpk enzalutamide through PO administration for 28 days (TGl=B.37%, T/C=93.22%) compared to the enzalutamide efficacies on LNCAP and 22RV1 CDX models. Western blot for androgen receptor ex­pression level in tumor tissues and ELISA assay for prostate specific androgen (PSA) level in serum are highly cor­related to the tumor volume of C4-2B Enz-R CDX models. The well characterized novel C4-2B Enz-R cell line and CDX model were aoorooriate for new drug discovery of anti-PCa drugs through AR pathway in vitro and in vivo.