SAR study culminates in a series of HDAC6 selective inhibitors featuring Schisandrin C-analogous Cap as potential immunomodulatory agents for cancer therapy

HDAC6 inhibitors (HDAC6is) represent an emerging therapeutic option for triggering anti-cancer immune response. In this work, a novel series of HDAC6is, derived from an in-house analog of the traditional Chinese medicine monomer Schisandrin C, were designed and synthesized for SAR study. Throughout the 29 target compounds, 24a, 24b and 24h exerted single-digit nanomolar enzymatic activity and remarkably elevated subtype selectivity compared to the clinically investigated HDAC6i Ricolinostat (Selectivity index = 3.3). In A549 tumor cells, 24h, as the representative in this series (IC50 = 7.7 nM; selectivity index = 31.4), was capable of reversing IL-6-mediated PD-L1 upregulation, highlighting its immunomodulatory capability. Importantly, unlike numerous other hydroxamate-based HDACis, 24h displayed an acceptable oral bioavailability in SpragueDawley rats, along with high plasma exposure, long elimination half-life and slow clearance. With the aforementioned attractive performance, 24h deserves further in vivo investigation as an immunomodulatory therapeutic agent for batting human malignance.