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

被引：19

作者：

Allegretti, Paul A. ^{[1
,2
,3
]}

Horton, Timothy M. ^{[1
,2
,3
,4
]}

Abdolazimi, Yassan ^{[1
,2
]}

Moeller, Hannah P. ^{[1
,2
,5
]}

Yeh, Benjamin ^{[1
,2
]}

Caffet, Matthew ^{[3
]}

Michel, Guillermina ^{[1
,2
]}

Smith, Mark ^{[3
]}

Annes, Justin P. ^{[1
,2
,3
,6
]}

机构：

[1] Stanford Univ, Dept Med, Stanford, CA 94305 USA

[2] Stanford Univ, Div Endocrinol, Stanford, CA 94305 USA

[3] Stanford Univ, Stanford ChEM H, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Chem, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA

[6] Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2020年 / 28卷 / 01期

关键词：

beta-cell replication; beta-cell regeneration; Dual-specificity tyrosine-regulated kinase 1A (DYRK1A); Diabetes; Medicinal chemistry; AURORA-B-KINASE; ANTITUMOR-ACTIVITY; SELECTIVE INHIBITOR; ADENOSINE KINASE; IN-VITRO; GROWTH; MASS; TURNOVER; PANCREAS; PROLIFERATION;

D O I：

10.1016/j.bmc.2019.115193

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：20

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