Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

TY - JOUR

T1 - Mining Public Domain Data to Develop Selective DYRK1A Inhibitors

AU - Henderson, Scott H.

AU - Sorrell, Fiona

AU - Bennett, James

AU - Hanley, Marcus T.

AU - Robinson, Sean

AU - Hopkins Navratilova, Iva

AU - Elkins, Jonathan M.

AU - Ward, Simon E.

N1 - Copyright © 2020 American Chemical Society.

PY - 2020/8/13

Y1 - 2020/8/13

N2 - Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

AB - Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor.

KW - DYRK1A

KW - polypharmacology

KW - chemoinformatics

KW - selectivity

UR - https://www.scopus.com/pages/publications/85090563709

U2 - 10.1021/acsmedchemlett.0c00279

DO - 10.1021/acsmedchemlett.0c00279

M3 - Article

C2 - 32832032

SN - 1948-5875

VL - 11

SP - 1620

EP - 1626

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 8

ER -