Discovery of Novel and Highly Potent Wee1 and HDAC Dual-Target Inhibitors for the Treatment of Acute Myeloid Leukemia.

Inhibiting Wee1 is recognized as an effective strategy for treating acute myeloid leukemia (AML). However, the compensatory activation of CHK1 may reduce the efficacy of Wee1 inhibitors in AML treatment. Given that histone deacetylase (HDAC) inhibitors downregulate CHK1 expression, the simultaneous inhibition of both Wee1 and HDAC could yield a synergistic effect. Based on this premise, we designed and synthesized a series of dual-targeting compounds by the pharmacophore combination strategy. Notably, compound 23f demonstrates significant inhibitory activity against both Wee1 and HDACs, effectively inhibiting the proliferation of MV4-11 cells. Furthermore, in the MV4-11 xenograft model, compound 23f demonstrates remarkable antitumor efficacy (TGI = 82%) at a dose of 60 mg/kg. This study identifies compound 23f as a potent dual-target inhibitor of Wee1 and HDAC, offering a novel option for the treatment of AML. Additionally, it serves as a probe for further investigation into the synergistic mechanisms between these two targets.

• Publication year

  2025

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2025-10-28

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.5c01789PMID 41147365
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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