Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for PMP22 Gene-Dosage Disorder Drug Discovery was written by Martinez, Natalia J.;Braisted, John C.;Dranchak, Patricia K.;Moran, John J.;Larson, Hunter;Queme, Bryan;Pak, Evgenia;Dutra, Amalia;Rai, Ganesha;Cheng, Ken Chih-Chien;Svaren, John;Inglese, James. And the article was included in ACS Pharmacology & Translational Science in 2021.Product Details of 11024-24-1 This article mentions the following:
Charcot-Marie-Tooth 1A (CMT1A) is the most common form of hereditary peripheral neuropathies, characterized by genetic duplication of the critical myelin gene Peripheral Myelin Protein 22 (PMP22). PMP22 overexpression results in abnormal Schwann cell differentiation, leading to axonal loss and muscle wasting. Since regulation of PMP22 expression is a major target of therapeutic discovery for CMT1A, we sought to establish unbiased approaches that allow the identification of therapeutic agents for this disease. Using genome editing, we generated a coincidence reporter assay that accurately monitors Pmp22 transcript levels in the S16 rat Schwann cell line, while reducing reporter-based false positives. A quant. high-throughput screen (qHTS) of 42 577 compounds using this assay revealed diverse novel chem. classes that reduce endogenous Pmp22 transcript levels. Moreover, some of these classes show pharmacol. specificity in reducing Pmp22 over another major myelin-associated gene, Mpz (Myelin protein zero). Finally, to investigate whether compound-mediated reduction of Pmp22 transcripts translates to reduced PMP22 protein levels, we edited the S16 genome to generate a reporter assay that expresses a PMP22-HiBiT fusion protein using CRISPR/Cas9. Overall, we present a screening platform that combines genome edited cell lines encoding reporters that monitor transcriptional and post-translational regulation of PMP22 with titration-based screening (e.g., qHTS), which could be efficiently incorporated into drug discovery campaigns for CMT1A. In the experiment, the researchers used many compounds, for example, Digitonin (cas: 11024-24-1Product Details of 11024-24-1).
Digitonin (cas: 11024-24-1) belongs to tetrahydropyran derivatives. Tetrahydropyran is a useful synthetic intermediate. Tetrahydropyranyl (THP-) ethers derived from the reaction of alcohols and dihydropyran are common intermediates in organic synthesis. There is large number of marine macrolide natural products that contain tetrahydropyran and tetrahydrofuran ring together. For instance, goniodomin A (actin targeting polyether), prorocentrolide (toxin halistatins), and percentotoxineProduct Details of 11024-24-1
Referemce:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics