Co-crystal-guided HDAC6 inhibitors that reach the L2 loop and trigger autophagy in lung cancer cells
- Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
- Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
- One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.
💡 Points
Grabbing the L2 loop is the obvious handle for isoform selectivity: the CD2 pocket is conserved, the loop is not. Acetylated tubulin up and histones flat is the readout I want before believing a selectivity claim. I'd still ask for a broad HDAC panel and some PK before getting excited about the autophagy story.