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

Yuting Sun; Hui Yang; Jiaqi Yuan; Limin Wang; Shanshan Song; Rongrong Chen; Xubin Bao; Li Jia; Tiantian Yang; Xiaofei Zhang; Qian He; Yong Gan; Zehong Miao; Jinxue He; Chunhao Yang

doi:10.1021/acs.jmedchem.3c00821

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

J Med Chem. 2023 Sep 14;66(17):12284-12303. doi: 10.1021/acs.jmedchem.3c00821. Epub 2023 Aug 21.

Authors

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 Zhang¹, Qian He¹, Yong Gan^{1

2

4}, Zehong Miao^{3

2}, Jinxue He^{3

2}, Chunhao Yang^{1

2}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
BRCA1 Protein*
BRCA2 Protein*
Humans
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Rats

Substances

BRCA1 protein, human
BRCA2 protein, human
BRCA1 Protein
BRCA2 Protein
Poly(ADP-ribose) Polymerase Inhibitors