Millepachine hybrid hits tubulin and HDAC8 together in ovarian cancer models
- The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
- Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
- It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.
💡 Points
HDAC8 is a less crowded choice than the usual HDAC6/class I pairing, and pairing it with a tubulin binder is mechanistically coherent. My worry is the classic one for dual hybrids: the two activities rarely scale together, so I'd want evidence that HDAC8 inhibition, not just the tubulin arm, contributes to the in vivo effect.