Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B

Author(s):Show less -

Segretti, Natanael D. ; Takarada, Jessica E. ; Ferreira, Marcos A., Jr. ; Santiago, Andre da Silva ; Teodoro, Bruno V. M. ; Damiao, Mariana C. F. C. B. ; Godoi, Paulo H. ; Cunha, Micael R. ; Fala, Angela M. ; Ramos, Priscila Z. ; Ishikawa, Eloisa E. ; Mascarello, Alessandra ; Serafim, Ricardo A. M. ; Azevedo, Hatylas ; Guimaraes, Cristiano R. W. ; Counago, Rafael M.

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry Letters; v. 68, p. 6-pg., 2022-07-15.

Abstract

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. (AU)

• FAPESP's process: 19/14275-8 - Structural analysis of the kinase proteins PRPF4 and DYRK1B, from the CMGC family, and identification of small compound inhibitors
• Grantee: André da Silva Santiago
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/04853-4 - Study of the therapeutic potential of new modulators of the lysosomal calcium channel hTRPML1
• Grantee: Micael Rodrigues Cunha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 16/25320-6 - Design and synthesis of inhibitors for understudied protein kinases related to RNA and epigenetics
• Grantee: Ricardo Augusto Massarico Serafim
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants