Macrophage-Centric Phenotypic Screening Identifies Tetrazolone-Based HDAC6 Inhibitors That Reprogram the Tumor Immune Microenvironment and Improve Immune Checkpoint Blockade

  • J Med Chem. 2026 Jun 11;69(11):12870-12897. doi: 10.1021/acs.jmedchem.5c02453.
Nithya Gajendran  1 ,  Manasa Suresh  1 ,  Sebastian J Marquez R  2 ,  Sruthi Mohan  2 ,  Tim Ponsot  2 ,  David Quiceno-Torres  1 ,  Mario A Noboa  2 ,  Bryan T Weselman  1 ,  Xintang Li  1 ,  Marie Durr  1 ,  Zora Novakova  3 ,  Mike Schutkowski  4 ,  Matias Hepp  5 ,  Satish Noonepalle  1 ,  Cyril Barinka  3 ,  Duncan J Wardrop  2 ,  Alejandro Villagra  1  5
Affiliations
  • 1. Georgetown University, Washington, District of Columbia 20057, United States.
  • 2. University of Illinois Chicago, Chicago, Illinois 60607, United States.
  • 3. Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic.
  • 4. Charles Tanford Protein Center, Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany.
  • 5. Laboratorio de Investigación en Ciencias Biomédicas, Departamento de Ciencias Básicas y Morfología, Facultad de Medicina, Universidad Católica de la Santísima Concepción, 2850 Concepción, Chile.
PMID: 42212676 DOI: 10.1021/acs.jmedchem.5c02453
Abstract

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment (TME) and influencing the outcomes of immunotherapy. However, most drug screening strategies emphasize tumor cell cytotoxicity and neglect immune effector modulation. Here, we describe a macrophage-centric phenotypic screening platform to identify selective HDAC6 inhibitors that reprogram TAMs toward an antitumor phenotype. Building on the HDAC6 Inhibitor SS-208, we synthesized a novel class of tetrazolone-based compounds with potent selectivity and minimal cytotoxicity. Among these, SM-06-09 emerged as a lead candidate, showing subnanomolar HDAC6 inhibition, enhanced macrophage phagocytosis, antigen presentation, and T-cell activation in vitro. In a syngeneic melanoma model, SM-06-09 suppressed tumor growth and promoted M1-like TAM polarization. Combination with anti-PD-1 therapy further enhanced immune infiltration, increased effector memory and central memory T-cells, and improved antitumor efficacy. This study establishes a functional screening framework for identifying immunomodulatory compounds and supports the clinical potential of macrophage-targeted HDAC6 inhibitors as adjuncts to immune checkpoint blockade.

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