2. Academic Validation
  3. Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis

Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis

  • Sci Rep. 2023 Apr 14;13(1):6118. doi: 10.1038/s41598-023-32854-4.
Frances M Bashore 1,  Ariana B Marquez 2,  Apirat Chaikuad 3 4,  Stefanie Howell 1,  Andrea S Dunn 5,  Alvaro A Beltran 2 6,  Jeffery L Smith 1,  David H Drewry 1 7,  Adriana S Beltran 2 8,  Alison D Axtman 9
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 2 Human Pluripotent Cell Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
  • 4 Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strabe 15, 60438, Frankfurt, Germany.
  • 5 Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 6 Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 7 UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 8 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 9 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. alison.axtman@unc.edu.
PMID: 37059819 DOI: 10.1038/s41598-023-32854-4
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.

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