Dual Histone Deacetylase/PD-1/PD-L1 Inhibitors Reprogram Tumor−Immune Interactions and Are Effective in Therapy-Resistant Melanoma

Abstract Epigenetic modulators and immune checkpoint inhibitors represent two major therapeutic avenues in oncology, yet resistance and recurrence limit their efficacy. To address this, we designed and synthesized a series of dual histone deacetylase (HDAC)/PD-1/PD-L1 inhibitors (compounds 1−6). Among them, compounds 4 (HDAC6-selective) and 5 (HDAC1−3-selective) emerged as the most promising, both disrupting the PD-1/PD-L1 interaction in the nanomolar range and reducing tumor cell viability in vitro. Compound 4 counteracted T cell exhaustion, reshaped the immune landscape in vivo by enhancing neutrophil and NK cell activity, and showed potent antitumor activity in human BRAF-mutated melanoma models, including vemurafenib-resistant cells. Compound 5 exhibited strong direct cytotoxicity and induced PD-L1 expression, highlighting complex checkpoint regulation. Collectively, these findings support dual HDAC/PD-1/PD-L1 inhibition as a strategy to reprogram tumor−immune interactions and overcome resistance, with differential isoform selectivity proving critical for translational optimization.

Authors

Institutions

Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-11-04
DOI
https://doi.org/10.1021/acs.jmedchem.6c01392
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Dual Histone Deacetylase/PD-1/PD-L1 Inhibitors Reprogram Tumor−Immune Interactions and Are Effective in Therapy-Resistant Melanoma

Carola Castiello, Francesco Fiorentino, Antonello Mai, Silvio Aprile et al.
Journal of Medicinal Chemistry
Histone Deacetylase Inhibitors Research
article

Dual Histone Deacetylase/PD-1/PD-L1 Inhibitors Reprogram Tumor−Immune Interactions and Are Effective in Therapy-Resistant Melanoma

Carola Castiello, Francesco Fiorentino, Antonello Mai, Silvio Aprile, Simona Donati, Clemens Zwergel, Enkeleta Berisha, Giulia Romagnoli, Alessandra Fragale, Tamara Giacomelli, Lucia Gabriele, Maria Buoncervello, Laura Lattanzi, Alessandra Pinzon Grimaldos, Silvia Piconese, Rossella Fioravanti, Sabrina Garbo, Cecilia Battistelli, Sérgio Valente, Felicia Grasso, Ilenia Pacella, Chiara Lambona, Alessia Raucci, Nicoletta Antonini, Tommaso Priamo
article en

Abstract

Abstract Epigenetic modulators and immune checkpoint inhibitors represent two major therapeutic avenues in oncology, yet resistance and recurrence limit their efficacy. To address this, we designed and synthesized a series of dual histone deacetylase (HDAC)/PD-1/PD-L1 inhibitors (compounds 1−6). Among them, compounds 4 (HDAC6-selective) and 5 (HDAC1−3-selective) emerged as the most promising, both disrupting the PD-1/PD-L1 interaction in the nanomolar range and reducing tumor cell viability in vitro. Compound 4 counteracted T cell exhaustion, reshaped the immune landscape in vivo by enhancing neutrophil and NK cell activity, and showed potent antitumor activity in human BRAF-mutated melanoma models, including vemurafenib-resistant cells. Compound 5 exhibited strong direct cytotoxicity and induced PD-L1 expression, highlighting complex checkpoint regulation. Collectively, these findings support dual HDAC/PD-1/PD-L1 inhibition as a strategy to reprogram tumor−immune interactions and overcome resistance, with differential isoform selectivity proving critical for translational optimization.

Journal of Medicinal Chemistry
Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Istituto Superiore di Sanità (IT), Piedmont University (US), Sapienza University of Rome (IT)
Openalex Percentile: Top 24%
Histone Deacetylase Inhibitors Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon