puc-header

Modulation of Tau Tubulin Kinases ((TTBK1 and TTBK2) Impacts Ciliogenesis

107 Pages Posted: 19 May 2022 Publication Status: Review Complete

See all articles by Frances Potjewyd

Frances Potjewyd

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium; University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Ariana B. Marquez

University of North Carolina (UNC) at Chapel Hill - Human Pluripotent Stem Cell Core

Apirat Chaikuad

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry

Stefanie Howell

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium

Andrea S. Dunn

University of North Carolina (UNC) at Chapel Hill - Department of Pharmacology

Alvaro A. Beltran

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Neuroscience

Jeffery L. Smith

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium

David H. Drewry

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium

Adriana S. Beltran

University of North Carolina (UNC) at Chapel Hill - Human Pluripotent Stem Cell Core

Alison Donnelly Axtman

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium; University of North Carolina (UNC) at Chapel Hill - Division of Chemical Biology and Medicinal Chemistry

More...

Abstract

Tau tubulin kinase 1 and 2 (TTBK1 and TTBK2) 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 to 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 KO in iPSCs, confirming an essential role for TTBK2 in ciliogenesis.

Keywords: kinase, IDG, TTBK1, TTBK2, small molecule, NanoBRET, crystal structure, cilia, induced pluripotent stem cells, ciliogenesis

Suggested Citation

Potjewyd, Frances and Marquez, Ariana B. and Chaikuad, Apirat and Howell, Stefanie and Dunn, Andrea S. and Beltran, Alvaro A. and Smith, Jeffery L. and Drewry, David H. and Beltran, Adriana S. and Axtman, Alison Donnelly, Modulation of Tau Tubulin Kinases ((TTBK1 and TTBK2) Impacts Ciliogenesis. Available at SSRN: https://ssrn.com/abstract=4114954 or http://dx.doi.org/10.2139/ssrn.4114954
This version of the paper has not been formally peer reviewed.

Frances Potjewyd

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium ( email )

Chapel Hill, NC
United States

University of North Carolina (UNC) at Chapel Hill - Center for Integrative Chemical Biology and Drug Discovery

Ariana B. Marquez

University of North Carolina (UNC) at Chapel Hill - Human Pluripotent Stem Cell Core ( email )

Chapel Hill, NC
United States

Apirat Chaikuad

Goethe University Frankfurt - Institute of Pharmaceutical Chemistry

Max-von-Laue-Str. 9
Frankfurt, D-60438
Germany

Stefanie Howell

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium ( email )

Andrea S. Dunn

University of North Carolina (UNC) at Chapel Hill - Department of Pharmacology ( email )

Alvaro A. Beltran

University of North Carolina (UNC) at Chapel Hill, School of Medicine, Department of Neuroscience ( email )

Jeffery L. Smith

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium ( email )

David H. Drewry

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium ( email )

Adriana S. Beltran

University of North Carolina (UNC) at Chapel Hill - Human Pluripotent Stem Cell Core ( email )

Alison Donnelly Axtman (Contact Author)

University of North Carolina (UNC) at Chapel Hill - Structural Genomics Consortium ( email )

Chapel Hill, NC
United States

University of North Carolina (UNC) at Chapel Hill - Division of Chemical Biology and Medicinal Chemistry ( email )

102 Ridge Road
Chapel Hill, NC 27514
United States

Click here to go to Cell.com

Paper statistics

Downloads
4
Abstract Views
185
PlumX Metrics