Novel idebenone analogs block Shc’s access to insulin receptor to improve insulin sensitivity

Autor: Xiao Song Jiang, James L. Graham, Chun Kiu Hui, Maurizio Prato, Chase Garcia, Sidney M. Hecht, Omar M. Khdour, Cristian Rosso, Giacomo Filippini, Gino A Cortopassi, David M. Fash, Alexey Tomilov, Peter J. Havel
Přispěvatelé: Hui, Chunkiu, Tomilov, Alexey, Garcia, Chase, Jiang, Xiaosong, Fash, David M., Khdour, Omar M., Rosso, Cristian, Filippini, Giacomo, Prato, Maurizio, Graham, Jame, Hecht, Sidney, Havel, Peter, Cortopassi, Gino
Rok vydání: 2020
Předmět:
0301 basic medicine
Src Homology 2 Domain-Containing
Transforming Protein 1
Ubiquinone
medicine.medical_treatment
RM1-950
Type 2 diabetes
Pharmacology
Novel insulin sensitizing agents
Diabetes Mellitus
Experimental
Rats
Sprague-Dawley
Mice
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Insulin
Idebenone
Sensitization
biology
Drug discovery
Chemistry
Small molecule therapeutics
General Medicine
medicine.disease
insuline receptor
Small molecule
Receptor
Insulin
Type 2 Diabetes
Rats
Metformin
Mice
Inbred C57BL
idebenone
Insulin receptor
030104 developmental biology
medicine.anatomical_structure
Diabetes Mellitus
Type 2
030220 oncology & carcinogenesis
biology.protein
Therapeutics. Pharmacology
Insulin Resistance
Shc blockers
medicine.drug
Zdroj: Biomedicine & Pharmacotherapy, Vol 132, Iss, Pp 110823-(2020)
ISSN: 0753-3322
DOI: 10.1016/j.biopha.2020.110823
Popis: There has been little innovation in identifying novel insulin sensitizers. Metformin, developed in the 1920s, is still used first for most Type 2 diabetes patients. Mice with genetic reduction of p52Shc protein have improved insulin sensitivity and glucose tolerance. By high-throughput screening, idebenone was isolated as the first small molecule 'Shc Blocker'. Idebenone blocks p52Shc's access to Insulin Receptor to increase insulin sensitivity. In this work the avidity of 34 novel idebenone analogs and 3 metabolites to bind p52Shc, and to block the interaction of p52Shc with the Insulin receptor was tested. Our hypothesis was that if an idebenone analog bound and blocked p52Shc's access to insulin receptor better than idebenone, it should be a more effective insulin sensitizing agent than idebenone itself. Of 34 analogs tested, only 2 both bound p52Shc more tightly and/or blocked the p52Shc-Insulin Receptor interaction more effectively than idebenone. Of those 2 only idebenone analog #11 was a superior insulin sensitizer to idebenone. Also, the long-lasting insulin-sensitizing potency of idebenone in rodents over many hours had been puzzling, as the parent molecule degrades to metabolites within 1 h. We observed that two of the idebenone’s three metabolites are insulin sensitizing almost as potently as idebenone itself, explaining the persistent insulin sensitization of this rapidly metabolized molecule. These results help to identify key SAR = structure-activity relationship requirements for more potent small molecule Shc inhibitors as Shc-targeted insulin sensitizers for type 2 diabetes.
Databáze: OpenAIRE
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