An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.

The Potential of Targeting DNA Repair Deficiency in Acute Myeloid Leukemia

“…Indeed, the levels of PARP1 itself may act as a biomarker with over-active PARP1 activity suggest that the tumour or leukemia may be responsive to PARP inhibition. Mutated BRCA is the most recognised and reliable biomarker for DNA repair deficiency but many others, including CDK12 and FA proteins, are also used in repair deficiency analysis [26]. Iniparib, was unsuccessful in a phase III trial when used as a treatment for triple-negative breast cancer [26].…”

“…Mutated BRCA is the most recognised and reliable biomarker for DNA repair deficiency but many others, including CDK12 and FA proteins, are also used in repair deficiency analysis [26]. Iniparib, was unsuccessful in a phase III trial when used as a treatment for triple-negative breast cancer [26]. It also proved to be ineffective in a phase II non-small lung cancer trial.…”

“…Despite early clinical trial doubts, one such inhibitor Olaparib has had very positive results in the treatment of BRCA-deficient ovarian cancer and in unfavorable AML [27]. More recently, the use of Olaparib has been approved as a treatment option for prostate cancer with either a BRCA or ATM mutation [26]. …”

Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions

“…1−3 PARP-1-mediated cell death, parthanatos, has been defined as a hallmark signature of neuronal cell death in Parkinson’s disease. 4 Additionally, PARP-1 has been shown to propagate the inflammatory cycle when hyperactivated by reactive oxygen species-induced DNA damage by rapidly catalyzing PAR which promotes NF-κB signal transduction.…”

“…1,5,6 However, these drugs are not CNS penetrant and are also cytotoxic because of the respective intrinsic anticancer mechanisms of each compound. 3 Recently, we demonstrated how the cytotoxic properties of olaparib can be greatly reduced when replacing piperazine with a 2,6-diazaspiro[3.3]heptane core; 7 however, the CNS uptake of this analogue is still under investigation. Therefore, it is important to understand why PARPis are not CNS penetrant and whether PARPis can be developed with reduced DNA damaging properties.…”