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
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
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.
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.
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