Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP‐ribose) polymerase‐1/2 inhibitors

Iwashita, Akinori; Hattori, Kouji; Yamamoto, Hirofumi; Ishida, Junya; Kido, Yoshiyuki; Kamijo, Kazunori; Murano, Keiko; Miyake, Hiroshi; Kinoshita, Takayoshi; Warizaya, Masaichi; Ohkubo, Mitsuru; Matsuoka, Naoki; Mutoh, Seitaro

doi:10.1016/j.febslet.2005.01.036

Cited by 71 publications

(56 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the quest for synthesizing PARP-2 specific inhibitors, the laboratory of Gilbert de Murcia suggested the targeting of a loop that is unique in PARP-2, [25,30]. Efforts to develop 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 highly PARP-2-selective compounds have given rise to inhibitors that have 10-60 fold higher affinity for PARP-2 as compared to PARP-1 [113][114][115][116][117]. One of these inhibitors, UPF-1069 that has 60 fold higher affinity towards PARP-2 than PARP-1, was shown to provide protection against cerebral ischemia [117].…”

Section: Parp-2 In Oxidative Stress-related Diseasesmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

show abstract

Section: Parp-2 In Oxidative Stress-related Diseasesmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Instead of a hydroxyl group, the N9 atom of the quinoxaline ring forms a water-mediated hydrogen bond to Glu1138. The structure of this inhibitor has also been analyzed in complex with PARP1 (PDB entry 1wok; Iwashita et al, 2005). It was suggested that the terminal phenyl group of this ligand could provide selective inhibition between PARP1 and PARP2.…”

Section: 23mentioning

confidence: 99%

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

Qiu

Lam

Voytyuk

et al. 2014

Acta Cryst D Biol Crystallogr

View full text Add to dashboard Cite

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting doublestranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated -catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrasespecific inhibitors.

show abstract

“…The importance of interdomain communication in DNAdependent activation is also demonstrated by Trp318 mutations at the HD-WGR-Zn3 domain interfaces, resulting in a catalytically inactive PARP1 without affecting DNA binding . Notably, the HD subdomain, implicated as a focal point for interdomain communication, is an important CAT domain structural element defining the size of the inhibitor-binding pocket, and sometimes directly interacting with bound inhibitors (Iwashita et al, 2005;Penning et al, 2010).…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

“…(C) Superpositions of the 33 PARP1 CAT domain structures from PDB indicate that the D-loop residue, Tyr889, can assume multiple side-chain conformations. Binding of a rigid stereospecific inhibitor (e.g., talazoparib) may sterically restrict the side-chain flexibility (PDB IDs: 4PJT, 4GV7, 4HHY, 4HHZ, 4L6S, 4DQY, 3GN7, 3L3L, 3L3M, 3GJW, 2RD6, 1WOK, 1UK0, and 1UK1) Kinoshita et al, 2004;Iwashita et al, 2005;Miyashiro et al, 2009;Gandhi et al, 2010;Penning et al, 2010;Langelier et al, 2012;Gangloff et al, 2013;Lindgren et al, 2013;Ye et al, 2013;Aoyagi-Scharber et al, 2014). (Ruf et al, 1998) and well characterized as a sequence-diverse element in the PARP superfamily Papeo et al, 2013;Steffen et al, 2013), may also contribute to the protein dynamics of the CAT domain that are implicated in the putative inhibitor-induced reverse-allosteric signaling.…”

Section: Structural Basis For Parp-dna Trappingmentioning

confidence: 99%

Trapping Poly(ADP-Ribose) Polymerase

Shen

Aoyagi-Scharber

Wang

2015

J Pharmacol Exp Ther

201

188

View full text Add to dashboard Cite

Recent findings indicate that a major mechanism by which poly (ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for singleagent and combination treatments.

show abstract

Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP‐ribose) polymerase‐1/2 inhibitors

Cited by 71 publications

References 21 publications

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

Trapping Poly(ADP-Ribose) Polymerase

Contact Info

Product

Resources

About