Abstract

Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that are expressed and mediate disease-relevant pathways predominantly in the brain. Distinct roles for TTBK1 and TTBK2 have been delineated. While efforts have been devoted to characterizing the impact of TTBK1 inhibition in diseases like Alzheimer’s disease and amyotrophic lateral sclerosis, TTBK2 inhibition has been less explored. TTBK2 serves a critical function during cilia assembly. Given the biological importance of these kinases, we designed a targeted library from which we identified several chemical tools that engage TTBK1 and TTBK2 in cells and inhibit their downstream signaling. Indolyl pyrimidinamine 10 significantly reduced the expression of primary cilia on the surface of human induced pluripotent stem cells (iPSCs). Furthermore, analog 10 phenocopies TTBK2 knockout in iPSCs, confirming a role for TTBK2 in ciliogenesis.

Details

Title
Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis
Author
Bashore, Frances M. 1   VIAFID ORCID Logo  ; Marquez, Ariana B. 2 ; Chaikuad, Apirat 3   VIAFID ORCID Logo  ; Howell, Stefanie 1   VIAFID ORCID Logo  ; Dunn, Andrea S. 4 ; Beltran, Alvaro A. 5 ; Smith, Jeffery L. 1   VIAFID ORCID Logo  ; Drewry, David H. 6   VIAFID ORCID Logo  ; Beltran, Adriana S. 7   VIAFID ORCID Logo  ; Axtman, Alison D. 1   VIAFID ORCID Logo 

1  University of North Carolina at Chapel Hill, Structural Genomics Consortium, UNC Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
2  University of North Carolina at Chapel Hill, Human Pluripotent Cell Core, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
3  Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Frankfurt, Germany (GRID:grid.7839.5) (ISNI:0000 0004 1936 9721); Goethe University Frankfurt, Structural Genomics Consortium, Buchmann Institute for Life Sciences, Frankfurt, Germany (GRID:grid.7839.5) (ISNI:0000 0004 1936 9721) 
4  University of North Carolina at Chapel Hill, Department of Computer Science, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
5  University of North Carolina at Chapel Hill, Human Pluripotent Cell Core, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina at Chapel Hill, Neuroscience Center, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
6  University of North Carolina at Chapel Hill, Structural Genomics Consortium, UNC Eshelman School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
7  University of North Carolina at Chapel Hill, Human Pluripotent Cell Core, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
Pages
6118
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-023-32854-4
ProQuest document ID
2801040418
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.