2. Academic Validation
  3. Discovery of new fungal jumonji H3K27 demethylase inhibitors for the treatment of Cryptococcus neoformans and Candida auris infections

Discovery of new fungal jumonji H3K27 demethylase inhibitors for the treatment of Cryptococcus neoformans and Candida auris infections

  • Eur J Med Chem. 2025 Jan 5:281:117028. doi: 10.1016/j.ejmech.2024.117028.
Xin Liu 1,  Wang Li 1,  Yang Liu 2,  Xiaoqing Wang 1,  Qiao Shi 1,  Wanzhen Yang 1,  Jie Tu 1,  Yan Wang 3,  Chunquan Sheng 4,  Na Liu 5
Affiliations

Affiliations

  • 1 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai, 200433, China.
  • 2 Department of Pharmacy, NO.971 Hospital of the People's Liberation Army Navy, 22 Minjiang Road, Qingdao, Shandong, 266071, China.
  • 3 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai, 200433, China. Electronic address: wangyansmmu@126.com.
  • 4 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai, 200433, China. Electronic address: shengcq@smmu.edu.cn.
  • 5 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai, 200433, China. Electronic address: liuna@smmu.edu.cn.
PMID: 39536495 DOI: 10.1016/j.ejmech.2024.117028
Abstract

Invasive Fungal infections have become a serious public health problem. To tackle the challenges of limited efficacy in Antifungal therapy and severe drug resistance, Antifungal drugs with new mechanisms of action are urgently needed. Our previous study identified JIB-04 to be an inhibitor of fungal Histone Demethylase (HDM). To promote target validation and inhibitor design, herein a series of new JIB-04 derivatives were designed and synthesized. After the establishment of structure-activity relationship, compound A4 was identified to possess potent Antifungal activity against Cryptococcus neoformans and Candida auris. Compared to lead compound JIB-04, compound A4 was a more potent HDM inhibitor and exhibited better water solubility, virulence factors inhibitory activity and in vivo Antifungal potency. Collectively, this study further confirmed that Fungal HDMs were potential Antifungal targets and compound A4 was a promising Antifungal lead compound.

Keywords

Antifungal agent; Candida auris; Cryptococcus neoformans; HDM inhibitors; JIB-04; Structural optimization; Virulence factor.

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