TY - JOUR
T1 - The ups and downs of Poly(ADP-ribose) Polymerase-1 inhibitors in cancer therapy–Current progress and future direction
AU - Zhao, Yue
AU - Zhang, Liu Xia
AU - Jiang, Ting
AU - Long, Jing
AU - Ma, Zhong Ye
AU - Lu, Ai Ping
AU - Cheng, Yan
AU - Cao, Dong Sheng
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (81972480) and HKBU Strategic Development Fund project (SDF19-0402-P02). The studies meet with the approval of the university’s review board.
Publisher copyright:
© 2020 Elsevier Masson SAS. All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Poly(ADP-ribose) Polymerase 1 (PARP1), one of the most investigated 18 membered PARP family enzymes, is involved in a variety of cellular functions including DNA damage repair, gene transcription and cell apoptosis. PARP1 can form a PARP1(ADP-ribose) polymers, then bind to the DNA damage gap to recruit DNA repair proteins, and repair the break to maintain genomic stability. PARP1 is highly expressed in tumor cells, so the inhibition of PARP1 can block DNA repair, promote tumor cell apoptosis, and exert antitumor activity. To date, four PARP1 inhibitors namely olaparib, rucaparib, niraparib and talazoparib, have been approved by Food and Drug Administration (FDA) for treating ovarian cancer and breast cancer with BRCA1/2 mutation. These drugs have showed super advantages over conventional chemotherapeutic drugs with low hematological toxicity and slowly developed drug resistance. In this article, we summarize and analyze the structure features of PARP1, the biological functions and antitumor mechanisms of PARP1 inhibitors. Importantly, we suggest that establishing a new structure-activity relationship of developed PARP1 inhibitors via substructural searching and the matched molecular pair analysis would accelerate the process in finding more potent and safer PARP1 inhibitors.
AB - Poly(ADP-ribose) Polymerase 1 (PARP1), one of the most investigated 18 membered PARP family enzymes, is involved in a variety of cellular functions including DNA damage repair, gene transcription and cell apoptosis. PARP1 can form a PARP1(ADP-ribose) polymers, then bind to the DNA damage gap to recruit DNA repair proteins, and repair the break to maintain genomic stability. PARP1 is highly expressed in tumor cells, so the inhibition of PARP1 can block DNA repair, promote tumor cell apoptosis, and exert antitumor activity. To date, four PARP1 inhibitors namely olaparib, rucaparib, niraparib and talazoparib, have been approved by Food and Drug Administration (FDA) for treating ovarian cancer and breast cancer with BRCA1/2 mutation. These drugs have showed super advantages over conventional chemotherapeutic drugs with low hematological toxicity and slowly developed drug resistance. In this article, we summarize and analyze the structure features of PARP1, the biological functions and antitumor mechanisms of PARP1 inhibitors. Importantly, we suggest that establishing a new structure-activity relationship of developed PARP1 inhibitors via substructural searching and the matched molecular pair analysis would accelerate the process in finding more potent and safer PARP1 inhibitors.
KW - Cancer
KW - DNA damage repair
KW - Matched molecular pair
KW - PARP1
KW - PARP1 inhibitors
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=85088402002&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112570
DO - 10.1016/j.ejmech.2020.112570
M3 - Review article
C2 - 32717529
AN - SCOPUS:85088402002
SN - 0223-5234
VL - 203
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 112570
ER -