A 5-azaindole TTBK1/2 probe with a matched negative control disrupts ciliogenesis
- The 5-azaindole inhibitor 13 is potent against tau tubulin kinases 1 and 2 and active in cells.
- In-cell kinome profiling showed few off-targets; follow-up NanoBRET work narrowed them to CDK11A/B, CK1δ and PIKfyve.
- A close analogue, compound 5, lacks in-cell TTBK affinity and serves as a negative control; compound 13 blocks TTBK2 autophosphorylation and impairs primary cilia formation in RPE-1 cells.
💡 Points
What I like here is the discipline: a kinome-wide in-cell selectivity map, honest naming of the CDK11 and PIKfyve liabilities, and a matched inactive control. That is what a probe should look like before anyone reads biology into a ciliogenesis phenotype. The CDK11 overlap is the caveat I'd test first, with an orthogonal chemotype.
Potent and Cell Active 5-Azaindole-based Tau Tubulin Kinase Inhibitors Disrupt Ciliogenesis ↗