2. Academic Validation
  3. Development of Biphenyl-Substituted Uracil-Based Hydroxamic Acids (UBHAs) as Potent HDAC Inhibitors with Pro-Apoptotic Activity in Leukemia and Prostate Cancer Cells

Development of Biphenyl-Substituted Uracil-Based Hydroxamic Acids (UBHAs) as Potent HDAC Inhibitors with Pro-Apoptotic Activity in Leukemia and Prostate Cancer Cells

  • J Med Chem. 2026 May 14;69(9):10060-10082. doi: 10.1021/acs.jmedchem.5c02737.
Francesco Fiorentino 1,  Giulio Bontempi 2 3,  Federica Michetti 2 3,  Valeria Pecci 4,  Emanuele Fabbrizi 5,  Daniela Passeri 6,  Letizia Corsetti 7,  Valentina Farini 8,  Fabrizio Casano 5,  Antimo Gioiello 9,  Antonella Di Sotto 7,  Roberto Pellicciari 6,  Donatella Del Bufalo 8,  Daniela Trisciuoglio 10,  Simona Nanni 4 11,  Raffaele Strippoli 2 3,  Antonello Mai 5,  Dante Rotili 12 13
Affiliations

Affiliations

  • 1 Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo 5, 00185 Rome, Italy.
  • 2 Department of Molecular Medicine, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 3 Gene Expression Laboratory, National Institute for Infectious Diseases, Lazzaro Spallanzani IRCCS, Via Portuense, 292, 00149 Rome, Italy.
  • 4 Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Rome, Italy.
  • 5 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo 5, 00185 Rome, Italy.
  • 6 TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy.
  • 7 Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 8 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Rome 00144, Italy.
  • 9 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122 Perugia, Italy.
  • 10 Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli, 4, Rome 00185, Italy.
  • 11 Fondazione "Policlinico Universitario A. Gemelli IRCCS", Largo Francesco Vito, 1, 00168 Rome, Italy.
  • 12 Department of Science, Roma Tre University, Viale Marconi 446, 00146 Rome, Italy.
  • 13 Biostructures and Biosystems National Institute (INBB), Via dei Carpegna 19, 00165 Rome, Italy.
PMID: 42059134 DOI: 10.1021/acs.jmedchem.5c02737
Abstract

Histone deacetylases (HDACs) regulate transcription by removing acetyl groups from lysines, and their dysregulation promotes Cancer. Clinically approved HDAC inhibitors show limited isoform selectivity, toxicity, and modest efficacy in solid tumors. We therefore designed and synthesized uracil-based hydroxamic acids (UBHAs) bearing systematic cap group and linker modifications. Several compounds achieved nanomolar inhibition, particularly against HDAC6, and reduced activity toward class I isoforms. Structure-activity relationships highlight that para-substituted phenyl moieties and four-carbon linkers enhance potency. Compounds 14a and 14b emerged as lead candidates, reducing Cancer cell viability at submicromolar doses while sparing noncancerous cells. In U937 cells, both promoted cell-cycle arrest, Apoptosis, and H3K9 and α-tubulin acetylation, alongside modulation of apoptosis-related genes and MicroRNAs. In prostate Cancer models, 14a inhibited AR- and AR+ cell proliferation, enhanced histone and tubulin acetylation, upregulated p21, and downregulated Bcl-2. These findings identify biphenyl-substituted UBHAs as promising therapeutics and probes to dissect HDAC biology.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z