Structure-based design of the approved drug zafirlukast identifies HLC40 as a potent WDR5 WIN-site inhibitor with antitumor efficacy

  • Bioorg Chem. 2026 Jul 15:176:109869. doi: 10.1016/j.bioorg.2026.109869.
Linchong He  1 ,  Congzhen Shen  1 ,  Cong Fan  1 ,  Yigui Li  1 ,  Siying Liu  2 ,  Jie Song  2 ,  Tao Zheng  1 ,  Xiaojie Huang  1 ,  Juqi Wen  1 ,  Jun Xu  1 ,  Ping Lan  1 ,  Jinrong Min  2 ,  Pinghua Sun  3 ,  Yunyuan Huang  4 ,  Xin Chen  5
Affiliations
  • 1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
  • 2. Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, PR China.
  • 3. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Institute for Safflower Industry Research, Key Laboratory of Xinjiang Phytomedicine Resource and Utilization (Ministry of Education), School of Pharmacy, Shihezi University, Shihezi 832003, China. Electronic address: [email protected].
  • 4. Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, PR China. Electronic address: [email protected].
  • 5. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: [email protected].
PMID: 42001591 DOI: 10.1016/j.bioorg.2026.109869
Abstract

WD40 repeat-containing protein 5 (WDR5) plays a critical role in chromatin-related processes, and its overexpression is associated with poor prognosis in multiple cancers, making it an attractive therapeutic target. Screening of an approved drug library identified zafirlukast (ZAF), an anti-asthmatic agent, as a binder to the WIN site of WDR5, inhibiting the Histone Methyltransferase activity of the MLL1 complex with an IC50 of 22.96 μM. Structure-based optimization yielded the candidate HLC40, which not only abolished its original CysLT1 receptor antagonism (IC50 > 5 μM) but also exhibited a 30-fold enhancement in MLL1 Histone Methyltransferase (HMT) inhibitory activity (IC50 = 0.82 μM). Consistent with these findings, HLC40 exhibited potent antiproliferation efficacy (IC50 = 7-8 μM) in AML cells and demonstrated significant efficacy in the MV4-11 xenograft model (TGI = 49.1% @ 30 mg/kg). Collectively, these results highlight that HLC40 is a promising WDR5-targeting candidate with high therapeutic potential for hematologic malignancies.

Keywords
Drug repurposing; Epigenetics; Hematologic malignancies; Structural modification; WDR5.
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