Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

Generation of highly potent DYRK1A-dependent inducers of human beta-Cell replication via Multi-Dimensional compound optimization. Bioorganic & medicinal chemistry Allegretti, P. A., Horton, T. M., Abdolazimi, Y., Moeller, H. P., Yeh, B., Caffet, M., Michel, G., Smith, M., Annes, J. P. 2019: 115193

Abstract

Small molecule stimulation of beta-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance beta-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human beta-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human beta-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human beta-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

View details for DOI 10.1016/j.bmc.2019.115193

View details for PubMedID 31757680