The ups and downs of Poly(ADP-ribose) Polymerase-1 inhibitors in cancer therapy–Current progress and future direction

• Published in: European journal of medicinal chemistry 2020-10, Vol.203, p.112570-112570, Article 112570
• Main Authors: Zhao, Yue, Zhang, Liu-Xia, Jiang, Ting, Long, Jing, Ma, Zhong-Ye, Lu, Ai-Ping, Cheng, Yan, Cao, Dong-Sheng
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; DNA damage repair; Drug Resistance, Neoplasm - drug effects; Humans; Matched molecular pair; Neoplasms - drug therapy; Neoplasms - enzymology; PARP1; PARP1 inhibitors; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112570

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. [Display omitted] •PARP1 is an abundant enzyme involved in various physiological and pathological cell activities.•PARP1 inhibitors can exert antitumor activity through the synthetic lethality and trapping DNA to target cancer cells.•Four FDA-approved PARP1 inhibitors have gained an important position in the treatment of breast and ovarian cancer.•Using substructure searching and matched molecular pair method, a more accurate SAR of PARP1 inhibitors was proposed.