Dual HDAC and PD-1/PD-L1 inhibitors tackle resistant melanoma
- Six hybrids combine histone deacetylase inhibition with PD-1/PD-L1 blockade in one molecule.
- Two leads differ in isoform preference, HDAC6-selective versus HDAC1-3; both disrupt the checkpoint pair and lower tumor cell viability in vitro.
- The HDAC6 lead eased T cell exhaustion, boosted neutrophil and NK activity in vivo, and worked in BRAF-mutant melanoma, including vemurafenib-resistant cells.
- The HDAC1-3 lead was cytotoxic but raised PD-L1 expression, so isoform choice matters.
💡 Points Based on the abstract
Set against dosing an HDAC inhibitor alongside a checkpoint antibody, one hybrid sidesteps PK mismatch but pays in size and lipophilicity, with a hydroxamate warhead on a biphenyl-type PD-L1 binder. PD-1/PD-L1 disruption needs confirming by HTRF and a cellular assay. The PD-L1 rise from the HDAC1-3 lead is a useful warning; HDAC6 looks the series to push.