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Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization.

Abstract：

:Small molecule stimulation of β-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 β-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 β-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 β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Allegretti PA,Horton TM,Abdolazimi Y,Moeller HP,Yeh B,Caffet M,Michel G,Smith M,Annes JP

doi

10.1016/j.bmc.2019.115193

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

115193

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)31138-1

journal_volume

28

pub_type

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