TY - JOUR
T1 - Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B
AU - Segretti, Natanael D.
AU - Takarada, Jessica E.
AU - Ferreira, Marcos A.
AU - Santiago, Andre da Silva
AU - Teodoro, Bruno V. M.
AU - Damiao, Mariana C. F. C. B.
AU - Godoi, Paulo H.
AU - Cunha, Micael R.
AU - Fala, Angela M.
AU - Ramos, Priscila Z.
AU - Ishikawa, Eloisa E.
AU - Mascarello, Alessandra
AU - Serafim, Ricardo A. M.
AU - Azevedo, Hatylas
AU - Guimaraes, Cristiano R. W.
AU - Counago, Rafael M.
PY - 2022/7/15
Y1 - 2022/7/15
N2 - The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.
AB - The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.
KW - Dyrk1a
KW - Dyrkb
KW - Kinase inhibitors
KW - Protein kinases
KW - Structure-based compound development
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000800009100008&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1016/j.bmcl.2022.128764
DO - 10.1016/j.bmcl.2022.128764
M3 - Article
C2 - 35504513
SN - 0960-894X
VL - 68
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 128764
ER -
