Dual SYK-HDAC Inhibitor Elicits Striking Efficacy against Acute Myeloid Leukemia: Rational Design, Synthesis, and Biological Evaluation

  • J Med Chem. 2026 Jun 25;69(12):14275-14308. doi: 10.1021/acs.jmedchem.6c00039.
Anshul Mishra  1 ,  Wen-Bin Yang  2  3 ,  Tsu-Shao Liu  1 ,  Amandeep Thakur  1 ,  Ajmer Singh Grewal  4 ,  Jacek Marczyk  5  6 ,  Giovanni Stelitano  7 ,  Ram Sharma  1 ,  Mandeep Rana  1 ,  Gurpreet Singh  8 ,  Santosh Kumar Guru  9 ,  Goutam Rath  10 ,  Saurabh Chawla  11  12 ,  Jing Ping Liou  1  13 ,  Chun Hsu Pan  1 ,  Kunal Nepali  1  13
Affiliations
  • 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
  • 2. Research Center for Neuroscience, Taipei Medical University, Taipei 110031, Taiwan.
  • 3. Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei 110031, Taiwan.
  • 4. Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar 135001, Haryana, India.
  • 5. Ontonix S.r.l, 23100 Sondrio, Italy.
  • 6. BioDynLab Ltd., Toronto, Ontario M5B1Y4, Canada.
  • 7. Department of Biotechnology, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
  • 8. Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga 142001, Punjab, India.
  • 9. Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India.
  • 10. Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar 751003, Odisha, India.
  • 11. School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O. Bhimpur-Padanpur, Jatni, Khurda, Bhubaneswar 752050, Odisha, India.
  • 12. Homi Bhabha National Institute (HBNI), Training School Complex, Anushaktinagar, Mumbai 400094, India.
  • 13. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110031, Taiwan.
PMID: 42262889 DOI: 10.1021/acs.jmedchem.6c00039
Abstract

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.

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