Dual SYK-HDAC Inhibitor Elicits Striking Efficacy against Acute Myeloid Leukemia: Rational Design, Synthesis, and Biological Evaluation
High Resolution Image Download MS PowerPoint Slide An integrated transcriptomic and survival analysis led to the identification of SYK and HDAC isoforms as age- and FLT3-dependent prognostic markers in acute myeloid leukemia (AML). Driven by the aforementioned, our research group employed a classical ligand-based hybrid pharmacophore strategy to furnish dual-target hybrid frameworks. Antitumor profiling culminated in a tractable bifunctional agent (Compound 14, dual SYK-HDAC inhibitor) endowed with substantial cell growth inhibitory effects against MV4–11 cell lines (AML cell lines harboring FLT3-ITD mutations). Compound 14 downregulated the expression levels of p-SYK and modulated the expression levels of the biomarkers associated with intracellular HDAC inhibition. Transcriptomic profiling revealed significantly suppressed lipid-associated metabolic pathways with Compound 14 treatment. Moreover, Compound 14 demonstrated an impressive pharmacokinetic profile and exerted significant antitumor efficacy in the FLT3-ITD-positive AML xenograft mouse model ( approximately 80% decrease in tumor mass ). Also, biochemical blood analysis and histopathological studies revealed that Compound 14 demonstrated a good safety profile.
Authors
- Chun Pan (ORCID: https://orcid.org/0000-0001-8700-583X)
- Giovanni Stelitano (ORCID: https://orcid.org/0000-0002-5219-4770)
- Jing‐Ping Liou (ORCID: https://orcid.org/0000-0002-3775-6405)
- Kunal Nepali (ORCID: https://orcid.org/0000-0002-6443-7928)
- Amandeep Thakur
- Santosh Kumar Guru (ORCID: https://orcid.org/0000-0002-9287-1836)
- Jacek Marczyk
- Ajmer Singh Grewal (ORCID: https://orcid.org/0000-0002-2418-9616)
- Saurabh Chawla (ORCID: https://orcid.org/0000-0001-6841-4929)
- Gurpreet Singh (ORCID: https://orcid.org/0000-0002-1421-3782)
- Wenbin Yang (ORCID: https://orcid.org/0000-0001-5056-7070)
- Anshul Mishra
- Mandeep Rana
- Tsu-Shao Liu
- Goutam Rath
- Ram Sharma
Institutions
- National Institute of Science Education and Research (IN)
- Siksha O Anusandhan University (IN)
- Homi Bhabha National Institute (IN)
- University of Pavia (IT)
- American Pharmacists Association (US)
- Guru Gobind Singh Medical College and Hospital (IN)
- TiGenix (Spain) (ES)
- Applied Medical Technology (United States) (US)
- Indo Soviet Friendship College of Pharmacy (IN)
- Institute for Biodiversity (DE)
- Center for Neurosciences (US)
- Drug Discovery Laboratory (Norway) (NO)
- Baba Guru Nanak University (PK)
- Taipei Medical University (TW)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00039
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Israel Science Foundation
- Taipei Medical University
- Università degli Studi di Pavia
- National Institute of Science Education and Research
- Homi Bhabha National Institute
- National Institute of Pharmaceutical Education and Research, Raebareli
- National Science and Technology Council
- Directorate for Biological Sciences