2. Academic Validation
  3. Design, synthesis and biological evaluation of novel PARP inhibitors against acquired drug-resistance

Design, synthesis and biological evaluation of novel PARP inhibitors against acquired drug-resistance

  • Eur J Med Chem. 2025 Dec 20:304:118507. doi: 10.1016/j.ejmech.2025.118507.
Yuting Sun 1,  Minghao Cao 2,  Xiaofei Zhang 1,  Xiajuan Huan 2,  Qian He 3,  Xubin Bao 2,  Zehong Miao 2,  Jinxue He 4,  Chunhao Yang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 2 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 4 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 41448044 DOI: 10.1016/j.ejmech.2025.118507
Abstract

PARP1 is the most extensive studied member of the PARPs and plays a critical role in maintaining genomic stability. The discovery of the synthetic lethality mechanism has promoted the development of PARPi. However, as the indication of PARPi expands, the issue of drug-resistance urgently needs to be addressed. Herein, through systematic optimization of YCH1899, a series of novel PARPi were designed and synthesized. Among them, YCH3292 not only exhibited robust antiproliferative activity against Capan-1/TP cells (IC50 = 0.23 nM), but also possessed an acceptable pharmacokinetic profile. Studies on the cellular mechanism revealed that it could induce DSB and activate innate immune signaling pathways. More importantly, YCH3292 was determined to be an attractive lead compound, which could overcome acquired resistance to existing PARPi and elicit antitumor immune responses in mouse tumor models.

Keywords

Anti-drug resistance; Antitumor immune; PARP inhibitor; Synthetic lethality.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180809
    PARP1/2 Inhibitor