PARP INHIBITOR: A MULTI PURPOSE AGENT

by Selleckchem | Jul 23 2012

PARP INHIBITOR AND ITS APPLICATIONS:
Poly ADP-ribose polymerases or PARP are translated by the PARP genes which are a part of human genome. PARP are vital proteins for some of the most important functions such as DNA repair mechanism and apoptosis. There are many reports of research in which a close relation of PARP inhibition is noted with BRCA1 and BRCA2 which are associated with onset of ovarian and breast cancer. Based on these research reports PARP inhibition has become a novel tool for the treatment of different types of cancers and tumors [1]. PARP inhibitors have shown efficient results against BRCA genes. PARP protein inhibitor has unique property of not affecting normal cell; therefore these inhibitors are specific for cancer cells. The choice for cancer treatment with least side effects is becoming famous due to PARP inhibitors which are potent anti cancer agents.

PROPERTIES OF PARP INHIBITORS:
Some of the antagonists and agonists are used for the determination of PARP such as TGZ and 15d-PGJ2, this task is not easy in research or in development fields [2]. During preclinical trials the efficiency of PARP inhibitors has been determined however if someone is willing to purchase PARP inhibitor one can contact to the respective suppliers. Different kits are available for the assessment of PARP inhibitor functions prior and after administration. PARP inhibitor can also be assessed by using siRNA screening where as another direct method is also there for quantification [4]. During in vivo studies AG14361, NU1025 and 3-aminobenzamide were analyzed against cancer of breast and it was reported that there is a strong relation between breast cancer and PARP inhibitor. The effect of these inhibitors was also studied on a mouse model deficient with BRCA1 mammary cancer cells [5]. There are many PARP inhibitors but among these PJ34 ABT888, BSI-201, 5-AIO AZD2281 or Olaparin are important to mention.

PARP INHIBITORS IN CLINICAL TRIALS:
Although there are many compounds which are under the category of PARP inhibitors but only 8 are being evaluated under clinical trials [6]. AZD2281 is a PARP inhibitor in clinical trials which showed anti cancer activity and it also inhibited the breast cancer cell proliferation by acting on BRCA in a mice model which was genetically induced to have breast cancer [7]. And during phase II of clinical trials it was also administered against BRCAness and ovarian cancer [8]. Beyond the cancer treatment PJ34 was also found to act as anti-strok agent when studied on in vitro or in vivo models [9]. In TNBC patients a PARP inhibitor BSI-201 was used in combination with Carboplatin and Gemcitabine and results were promising [10]. And for the treatment of ischemic patients 5-AIQ was administered which resulted in outstanding results [11]. Temozolomide was co administered with a PARP inhibitor known as AG-014699 against carcinomas during clinical phase I and proved as an effective inhibitor [12].

REFERENCES:
1. Rouleau M, e.a., PARP inhibition: PARP1 and beyond. Nature Reviews Cancer, 2010).
2. Liu JJ, e.a., Downregulation of cyclooxygenase-2 expression and activation of caspase-3 are involved in peroxisome proliferator-activated receptor-γ agonists induced apoptosis in human monocyte leukemia cells in vitro. Annals of Hematology, 2007.
3. Turner NC, e.a., A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. The EMBO Journal, 2008.
4. Putt KS, e.a., Direct Quantitation of Poly(ADP-Ribose) Polymerase (PARP) Activity as a Means to Distinguish Necrotic and Apoptotic Death in Cell and Tissue Samples. ChemBioChem, 2005.
5. Soto JA, e.a., The Inhibition and Treatment of Breast Cancer with Poly (ADP-ribose) Polymerase (PARP-1) Inhibitors. Int J Biol Sci., 2006.
6. Drew Y, P.R., PARP inhibitors in cancer therapy: Two modes of attack on the cancer cell widening the clinical applications. Drug Resistance Updates, 2009.
7. Rottenberg S, e.a., High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. PNAS, 2008.
8. Audeh MW, e.a., Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol, 2009.
9. Abdelkarim GE, e.a., Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med., 2001.
10. O'Shaughnessy J, e.a., Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol, 2009.
11. Filipe HM, e.a., The novel PARP inhibitor 5-aminoisoquinolinone reduces the liver injury caused by ischemia and reperfusion in the rat. . International Medical Journal of Experimental and Clinical Research, 2002.
12. Plummer R, e.a., First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors. Clinical Cancer Research, 2005.

Cat.No.	Product Name	Information
S1060	Olaparib (AZD2281)	Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations.
S1087	Iniparib (BSI-201)	Iniparib (BSI-201, NSC-746045, IND-71677) is a PARP1 inhibitor with demonstrated effectiveness in triple-negative breast cancer (TNBC). Phase 3.
S2178	AG-14361	AG14361 is a potent inhibitor of PARP1 with K_i of <5 nM in a cell-free assay. It is at least 1000-fold more potent than the benzamides.
S1004	Veliparib (ABT-888)	Veliparib (ABT-888, NSC 737664) is a potent inhibitor of PARP1 and PARP2 with K_i of 5.2 nM and 2.9 nM in cell-free assays, respectively. It is inactive to SIRT2. Veliparib increases autophagy and apoptosis. Phase 3.