Small molecule dual inhibitors of HDAC6/HSP90 as potential anticancer therapeutics: an overview of design rationality...

The inherent limitations of single-target cancer therapies, including drug resistance, toxicity, and inadequate efficacy against heterogeneous tumors, have catalyzed the strategic shift toward multi-targeted agents. The synergistic interplay between histone deacetylase 6 (HDAC6) and heat shock protein 90 (HSP90), two pivotal nodes in oncogenic signaling, presents a compelling rationale for dual inhibition. HDAC6 epigenetically silences tumor suppressors and regulates cell motility, while HSP90 stabilizes a vast array of oncoproteins. Their concurrent inhibition disrupts this powerful axis, promoting the degradation of oncogenic clients, reversing epigenetic silencing, overcoming drug resistance, and inducing apoptosis. This review comprehensively explores the rationale and recent advancements in the medicinal chemistry of HDAC6/HSP90 dual inhibitors. Through the analysis of diverse chemotypes, including hybrid hydroxamate-based scaffolds, fused heterocyclic systems, and bicyclic hydrophobic core derivatives, critical structure-activity relationship (SAR) principles have been elucidated. The integration of four key pharmacophoric elements is preferred for achieving balanced, nanomolar potency: a hydroxamate zinc-binding group (ZBG), a flexible C6-C8 alkyl linker, an aromatic cap group, and an integrated lipophilic resorcinol-based motif for HSP90 binding. This work underscores the immense potential of HDAC6/HSP90 dual inhibitors as a novel, synergistic, and polypharmacological strategy for cancer therapy, providing a clear roadmap for their rational design and future optimization.