TY - JOUR
T1 - Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2
AU - Serafim, Ricardo A. M.
AU - de Souza Gama, Fernando H.
AU - Dutra, Luiz A.
AU - dos Reis, Caio V.
AU - Vasconcelos, Stanley N. S.
AU - Santiago, Andre da Silva
AU - Takarada, Jessica E.
AU - Di Pillo, Fulvia
AU - Azevedo, Hatylas
AU - Mascarello, Alessandra
AU - Elkins, Jonathan M.
AU - Massirer, Katlin B.
AU - Gileadi, Opher
AU - Guimaraes, Cristiano R. W.
AU - Counago, Rafael M.
PY - 2019/9/12
Y1 - 2019/9/12
N2 - Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.
AB - Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.
KW - Vaccinia-related kinases
KW - Difluorophenol
KW - Kinase inhibitors
KW - Pyridine
KW - Structure-based compound development
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000486360800004&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1021/acsmedchemlett.9b00082
DO - 10.1021/acsmedchemlett.9b00082
M3 - Article
C2 - 31531195
SN - 1948-5875
VL - 10
SP - 1266
EP - 1271
JO - Acs Medicinal Chemistry Letters
JF - Acs Medicinal Chemistry Letters
IS - 9
ER -
