Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity
| Autor: | Jonnell C. Small, Aidan Joblin-Mills, Kaycee Carbone, Maria Kost-Alimova, Kumiko Ayukawa, Carol Khodier, Vlado Dancik, Paul A. Clemons, Andrew B. Munkacsi, Bridget K. Wagner |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | ACS Chemical Biology. 17:1131-1142 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.2c00052 |
| Popis: | Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity. |
| Databáze: | OpenAIRE |
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