Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.

Jin-Xue He,Bing Xiong,Ying-Qing Wang,Cun Tan,Meng Wang,Yi Su,Chuan-Huizi Chen,Qian He,Jian Ding,Yi Chen,Yuting Wang ,Shanshan Song ,Xuemei Liao ,Yang Xia ,Xiaohua Li ,Yanyan Shen ,Linjiang Tong ,Chunhao Yang ,Xiao Li Lu ,Zhiwei Gao ,Xiaoyan Chen ,Xia‐Juan Huan ,Yiming Sun ,Ze‐Hong Miao

doi:10.18632/oncotarget.13749

Abstract

The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced γH2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and γH2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%~100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.

Highlights

IntroductionDefects in DNA damage response (DDR) including DNA repair are one of primary reasons for such instability [2, 3]
Genomic instability is an important characteristic of cancers [1, 2]
Mechanistic studies indicated that mefuparib hydrochloride (MPH) inhibited the catalytic activity of PARP1 in a substrate (NAD+)competitive manner (Figure 1C) and reduced the formation of the resulting PAR (Figure 1D)

Summary

Introduction

Defects in DNA damage response (DDR) including DNA repair are one of primary reasons for such instability [2, 3]. Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the polymerization of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) on target proteins. Among this family, PARP1 and PARP2 are essential to base excision repair (BER) [5]. Approval of the PARP1/2 inhibitor AZD2281 ( known as olaparib) for the treatment of BRCA-deficient ovarian cancer in 2014 marked the successful establishment of such a therapeutic strategy for cancer in the clinic [3]

Methods

Results

Conclusion