2. Academic Validation
  3. YCH1899, a Highly Effective Phthalazin-1(2 H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors

YCH1899, a Highly Effective Phthalazin-1(2 H)-one Derivative That Overcomes Resistance to Prior PARP Inhibitors

  • J Med Chem. 2023 Aug 21. doi: 10.1021/acs.jmedchem.3c00821.
Yuting Sun 1 2,  Hui Yang 3 2,  Jiaqi Yuan 1 2,  Limin Wang 3 2,  Shanshan Song 3 2,  Rongrong Chen 1 4,  Xubin Bao 3 2,  Li Jia 3 2,  Tiantian Yang 1 2,  Xiaofei Zhang 1,  Qian He 1,  Yong Gan 1 2 4,  Zehong Miao 3 2,  Jinxue He 3 2,  Chunhao Yang 1 2
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.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046, China.
PMID: 37605459 DOI: 10.1021/acs.jmedchem.3c00821
Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) have significant efficacy in treating BRCA-deficient cancers, although resistance development remains an unsolved challenge. Herein, a series of phthalazin-1(2H)-one derivatives with excellent enzymatic inhibitory activity were designed and synthesized, and the structure-activity relationship was explored. Compared with olaparib and talazoparib, compound YCH1899 exhibited distinct antiproliferation activity against olaparib- and talazoparib-resistant cells, with IC50 values of 0.89 and 1.13 nM, respectively. Studies of the cellular mechanism revealed that YCH1899 retained sensitivity in drug-resistant cells with BRCA1/2 restoration or 53BP1 loss. Furthermore, YCH1899 had acceptable pharmacokinetic properties in rats and showed prominent dose-dependent antitumor activity in olaparib- and talazoparib-resistant cell-derived xenograft models. Overall, this study suggests that YCH1899 is a new-generation antiresistant PARPi that could provide a valuable direction for addressing drug resistance to existing PARPi drugs.

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