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

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

  • J Med Chem. 2025 Nov 13;68(21):22845-22873. doi: 10.1021/acs.jmedchem.5c01789.
Wenhui Zhang 1,  Wenxin Yan 2 3,  Tianyi Wei 1,  Sai Che 1,  Yangqian Sun 1,  Aohua Xiao 1,  Jiayu Wu 1,  Yunzhen Zhan 1,  Hongmei Li 4,  Tao Lu 4,  Yungen Xu 2 3 4,  Hongfeng Gu 2 3,  Hui Huang 1,  Jinsong Han 1 5
Affiliations

Affiliations

  • 1 National R&D Center for Chinese Herbal Medicine Processing, College of Engineering, China Pharmaceutical University, Nanjing 211198, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing 210009, China.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
PMID: 41147365 DOI: 10.1021/acs.jmedchem.5c01789
Abstract

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.

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