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

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.

Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

“…The DSB and SSB data were from the 60-min time point in (d) and Supporting Information Figure S4d and S6d. 5,6,13,38,43,44 Because the autoP-ARylation of PARP1 on DNA directly contributes to its dissociation from DNA, 37 the FA models can reflect the inhibition degree of the polymerase activity of the PARP1 protein that binds to DNA by PARPis. capability of PARPis in inhibiting the dissociation of PARP1 from DNA in cell-free DSB (r = 0.9984; p < 0.0001) and SSB (r = 0.9849; p = 0.0022) FA models and their cytotoxicity in 17 HR-deficient cell lines.…”

“…5,6,16,19,20 PARP1 inhibition assays in cell-free systems 5,6,16,19,20 PARP1 inhibition assays in cell-free systems…”

“…5,6 However, the results of this approach show a very low correlation with their ability to induce cytotoxicity in HR-deficient cancer cells. 5,6 However, the results of this approach show a very low correlation with their ability to induce cytotoxicity in HR-deficient cancer cells.…”

“…2,3 Three PARP1 inhibitors (PARPis), that is, olaparib, rucaparib and niraparib, have been approved for cancer therapy. 3,5,6 All the progress in PARPis makes understanding their precise modes of action become necessary. 3,5,6 All the progress in PARPis makes understanding their precise modes of action become necessary.…”

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

“…7 PTEN-deficient tumor cells are sensitive to PARPi. [8][9][10][11] For example, PTEN-deficient glioblastoma U87MG and U251 cells show different degrees of sensitivity to olaparib, [12][13][14] simmiparib 13 and mefuparib hydrochloride. 14 The U251 cell line has been used extensively and its sensitivity to PARPi, including olaparib and simmiparib, is higher than that of the U87MG cell line.…”