Preclinical Characterization of SDFZ‐8, a Highly Potent HDAC1 Inhibitor, for Cancer Immunotherapy

TL;DR

This paper introduces SDFZ-8, a powerful HDAC1 inhibitor, which boosts cancer immunotherapy by enhancing antitumor immunity and synergizing with PD-L1 blockade.

Contribution

The novel quinoline derivative SDFZ-8 is identified as a highly potent HDAC1 inhibitor with strong antiproliferative and immunostimulatory effects.

Findings

SDFZ-8 inhibits HDAC1 with an IC50 of 0.4 nM and induces cell apoptosis.

SDFZ-8 enhances antitumor immunity by activating T cells and M1 macrophages.

Combining SDFZ-8 with PD-L1 blockade results in synergistic antitumor effects.

Abstract

The histone deacetylases (HDACs) family plays a critical role in tumorigenesis and has been identified as having a significant impact on tumor immunity. Herein, we employed a fragment‐centric structure‐based design platform, leading to the discovery of SDFZ‐8 as a highly potent HDAC1 inhibitor (IC50 = 0.4 nM). SDFZ‐8 exhibits strong antiproliferative effects by enabling histone acetylation and inducing cell apoptosis. Crucially, SDFZ‐8 treatment led to a significant enhancement of antitumor immunity, as evidenced by increased activation of T cells, enhanced polarization of M1‐type macrophages, improved antigen presentation, and alleviation of the immunosuppressive tumor microenvironment. Specifically, we observed that SDFZ‐8 notably upregulated the expression of PD‐L1 in both tumor cells and tumor‐infiltrating lymphocytes, which is closely associated with its inhibition against HDAC1. Of particular interest, combining SDFZ‐8 with PD‐L1 blockade resulted in a synergistic antitumor effect surpassing that of either monotherapy. Taken together, our findings establish SDFZ‐8 as a novel HDAC1 inhibitor that concurrently targets tumor cells and immune evasion mechanisms, providing a rational combinatorial strategy to enhance cancer immunotherapy efficacy.

In this study, we designed a novel quinoline derivative as a potent HDAC inhibitor SDFZ‐8 and assessed its capability to enhance cancer immunotherapy, along with its potential synergistic effects with PD‐L1 blockade.

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