Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

Bo Yuan; Na Ye; Shan Shan Song; Yu Ting Wang; Zilan Song; Hua Dong Chen; Chuan Huizi Chen; Xia Juan Huan; Ying Qing Wang; Yi Su; Yan Yan Shen; Yi Ming Sun; Xin Ying Yang; Yi Chen; Shi Yan Guo; Yong Gan; Zhi Wei Gao; Xiao Yan Chen; Jian Ding; Jin Xue He; Ao Zhang; Ze Hong Miao

doi:10.1016/j.canlet.2016.11.010

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

Bo Yuan, Na Ye, Shan Shan Song, Yu Ting Wang, Zilan Song, Hua Dong Chen, Chuan Huizi Chen, Xia Juan Huan, Ying Qing Wang, Yi Su, Yan Yan Shen, Yi Ming Sun, Xin Ying Yang, Yi Chen, Shi Yan Guo, Yong Gan, Zhi Wei Gao, Xiao Yan Chen, Jian Ding, Jin Xue HeAo Zhang, Ze Hong Miao

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.

Original language	English (US)
Pages (from-to)	47-56
Number of pages	10
Journal	Cancer Letters
Volume	386
DOIs	https://doi.org/10.1016/j.canlet.2016.11.010
State	Published - Feb 1 2017
Externally published	Yes

Keywords

Growth inhibition
Homologous recombination repair defects
Olaparib
Patient-derived xenografts
Pharmacokinetics

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2016.11.010

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Yuan, B., Ye, N., Song, S. S., Wang, Y. T., Song, Z., Chen, H. D., Chen, C. H., Huan, X. J., Wang, Y. Q., Su, Y., Shen, Y. Y., Sun, Y. M., Yang, X. Y., Chen, Y., Guo, S. Y., Gan, Y., Gao, Z. W., Chen, X. Y., Ding, J., ... Miao, Z. H. (2017). Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. Cancer Letters, 386, 47-56. https://doi.org/10.1016/j.canlet.2016.11.010

Yuan, B, Ye, N, Song, SS, Wang, YT, Song, Z, Chen, HD, Chen, CH, Huan, XJ, Wang, YQ, Su, Y, Shen, YY, Sun, YM, Yang, XY, Chen, Y, Guo, SY, Gan, Y, Gao, ZW, Chen, XY, Ding, J, He, JX, Zhang, A & Miao, ZH 2017, 'Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials', Cancer Letters, vol. 386, pp. 47-56. https://doi.org/10.1016/j.canlet.2016.11.010

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title = "Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials",

abstract = "Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.",

keywords = "Growth inhibition, Homologous recombination repair defects, Olaparib, Patient-derived xenografts, Pharmacokinetics",

author = "Bo Yuan and Na Ye and Song, {Shan Shan} and Wang, {Yu Ting} and Zilan Song and Chen, {Hua Dong} and Chen, {Chuan Huizi} and Huan, {Xia Juan} and Wang, {Ying Qing} and Yi Su and Shen, {Yan Yan} and Sun, {Yi Ming} and Yang, {Xin Ying} and Yi Chen and Guo, {Shi Yan} and Yong Gan and Gao, {Zhi Wei} and Chen, {Xiao Yan} and Jian Ding and He, {Jin Xue} and Ao Zhang and Miao, {Ze Hong}",

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doi = "10.1016/j.canlet.2016.11.010",

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T1 - Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

AU - Yuan, Bo

AU - Ye, Na

AU - Song, Shan Shan

AU - Wang, Yu Ting

AU - Song, Zilan

AU - Chen, Hua Dong

AU - Chen, Chuan Huizi

AU - Huan, Xia Juan

AU - Wang, Ying Qing

AU - Su, Yi

AU - Shen, Yan Yan

AU - Sun, Yi Ming

AU - Yang, Xin Ying

AU - Chen, Yi

AU - Guo, Shi Yan

AU - Gan, Yong

AU - Gao, Zhi Wei

AU - Chen, Xiao Yan

AU - Ding, Jian

AU - He, Jin Xue

AU - Zhang, Ao

AU - Miao, Ze Hong

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.

AB - Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.

KW - Growth inhibition

KW - Homologous recombination repair defects

KW - Olaparib

KW - Patient-derived xenografts

KW - Pharmacokinetics

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AN - SCOPUS:84998546737

SN - 0304-3835

VL - 386

SP - 47

EP - 56

JO - Cancer Letters

JF - Cancer Letters

ER -

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

Abstract

Keywords

ASJC Scopus subject areas

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