TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models

	TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models
	Wang, Lei 1,2; Zhu, Xi 1,2; Li, Lili 1,3; Li, Lin 1,2; Fu, Li 1,2; Li, Yun 1,2; Fu, Haoyu 1,2; Chen, Xiaoyan 1,2; Lou, Liguang 1,2
刊名	AMERICAN JOURNAL OF CANCER RESEARCH
	2021
卷号	11 期号:4 页码:1632-1645
关键词	PARP DNA damage hematologic toxicity beta-glucuronidase tumor selectivity
ISSN号	2156-6976
通讯作者	Lou, Liguang(lglou@simm.ac.cn)
英文摘要	Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the cellular response to DNA damage and the inhibition of PARP causes synthetic lethality in homologous recombination (HR)-deficient cancer. Multiple PARP inhibitors have been developed and have shown remarkable clinical benefits. However, treatmentrelated toxicities, especially the hematologic toxicities, are common and restrict the clinical applications of PARP inhibitors. In this study, we designed the first glucuronide prodrug of PARP inhibitor, TSL-1502, based on a novel and highly potent PARP inhibitor TSL-1502M. TSL-1502M exhibited promising inhibitory activity on PARP1/2, significantly induced DNA double strand breaks, G2/M arrest and apoptosis in HR-deficient cells, selectively inhibited the proliferation of HR-deficient cancer cells and sensitized both HR-deficient and HR-proficient cancer cells to conventional chemotherapy. Notably, TSL-1502M was superior to olaparib, the first-in-class PARP inhibitor, in all these processes. TSL-1502 had no inhibitory effects on PARP1/2 itself, but could selectively liberate the active drug TSL-1502M in tumor after administration in nude mice. Moreover, TSL-1502 elicited significant more potent inhibitory effects than olaparib in HR-deficient tumors, and sensitized chemotherapy in both HR-deficient and HR-proficient tumors. No severe toxicities were caused by TSL-1502 in this study. Based on the encouraging preclinical antitumor activity and the selective decomposition characteristic of TSL-1502, a clinical phase I study was initiated in China, and an Investigational New Drug (IND) was granted by the US FDA. TSL-1502 could represent a new potential therapeutic choice of PARP inhibitors.
资助项目	National Natural Science Foundation of China[81502636] ; Shanghai Science and Technology Committee[18DZ2293200] ; Yunnan Provincial Science and Technology Department[2017ZF010]
WOS关键词	MAINTENANCE THERAPY ; OVARIAN-CANCER ; DOUBLE-BLIND ; POLY(ADP-RIBOSE) ; CHEMOTHERAPY ; COMBINATION ; MECHANISM ; TUMORS
WOS研究方向	Oncology
语种	英语
出版者	E-CENTURY PUBLISHING CORP
WOS记录号	WOS:000642167300009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296696]
专题	中国科学院上海药物研究所
通讯作者	Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Nanjing Univ Chinese Med, 138 Xianlin Rd, Nanjing 210023, Peoples R China
推荐引用方式 GB/T 7714	Wang, Lei,Zhu, Xi,Li, Lili,et al. TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2021,11(4):1632-1645.
APA	Wang, Lei.,Zhu, Xi.,Li, Lili.,Li, Lin.,Fu, Li.,...&Lou, Liguang.(2021).TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models.AMERICAN JOURNAL OF CANCER RESEARCH,11(4),1632-1645.
MLA	Wang, Lei,et al."TSL-1502, a glucuronide prodrug of a poly (ADP-ribose) polymerase (PARP) inhibitor, exhibits potent anti-tumor activity in preclinical models".AMERICAN JOURNAL OF CANCER RESEARCH 11.4(2021):1632-1645.