Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling

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

doi:10.1016/j.bmc.2005.09.061

Cited by 73 publications

(57 citation statements)

References 25 publications

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“…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.

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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...

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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.

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“…PARP-2, PARP-1'in bulunmadığı bölgelerde DNA tamirine yardım eder. Ancak PARP-2'deki DNA bağlama bölgesi, PARP-1'den farklıdır ve PARP-2'de merkez otomodifikasyon bölgesi yoktur (11).…”

Section: Poli (Adp-riboz) Polimerazlar (Parp'lar)unclassified

“…Bu sayede nörodejene-ratif hastalıklar olan Parkinson ve serebral iskemi tedavisinde yeni moleküller literatüre kazandırılmıştır. Kinazolinon analoglarının PARP-1/2 aktivite bulguları Tablo 8'de sunulmuştur (11).…”

Section: Parp İnhibitörü Moleküller üZerinde Araştırmalarunclassified

A New Approach in Cancer Treatment: Poly(ADP-Ribose) Polymerase-1 Inhibitors

Tok¹,

Kaymakçıoğlu²

2015

MUSBED

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Kanser tedavisinde yeni bir yaklaşım: Poli (ADP-riboz) polimeraz-1 inhibitörleri Genetik materyal olan DNA'da iç ve dış etkenler sonucu hasar oluşabilir. Normal bir hücrede bu hasarı onarabilecek çok sayıda tamir mekanizması vardır. Bunlardan biri de PARP-1 enzimidir. PARP-1, nikotinamid adenin dinükleotidden ADP-riboz yapılarını protein akseptörüne transfer eder. Böylece tek zincir DNA kırıkları onarılır. PARP-1'in inhibisyonu durumunda ise bu tek zincir DNA kırıkları onarılamaz ve çift zincir DNA kırıkları oluşur. Sonuçta hücre nekrozise ya da apoptozise gider. Kanser tedavisinde tümörlü hücrelerin PARP-1 inhibisyonuyla öldürülmesi amaçlanmaktadır. Bu amaçla son on yıl içinde çok sayıda çalışma yapılmış olup, günümüzde faz aşamasında bulunan ve piyasaya sürülmeyi bekleyen PARP-1 inhibitörleri mevcuttur. Bu derlemede, DNA'da oluşan hasarın hangi mekanizmalarla onarıldığı, PARP enzim ailesinin genomik bütünlüğü nasıl koruduğu ve kanser tedavisinde kullanılmak üzere geliştirilmiş PARP-1 inhibitörü kimyasal bileşiklerin yapıları hakkında bilgi verilmiştir.

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“…6,[8][9][10][11][12][13][14][15] Most PARP-1 inhibitors are competitive with NAD + and these structures are typically nicotinamide or benzamide analogs (Fig. 1).…”

Section: -7mentioning

confidence: 99%

“…The aromatic amide group of these compounds has been shown to form hydrogen bonds with the Gly-863 and Ser-904 amino acid residues of the PARP enzyme and also binds effectively to the aryl residues, Tyr907 and Tyr896, through a sandwiched hydrophobic π-π interaction. 8,10,13 We have recently disclosed tricyclic PARP-1 inhibitors, substituted thiopyrano [3,4-c]quinoline-9-carboxamide derivatives. 16 These compounds include a non-aromatic Aring and fit well to the active site even though their conformations are not flat.…”

Section: -7mentioning

confidence: 99%

Synthesis and Evaluation of Tricyclic Derivatives Containing a Non-Aromatic Amide as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors

Park

Chun

Choi

et al. 2011

Bulletin of the Korean Chemical Society

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A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors were successfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one 23c displayed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC 50 = 0.142 µM, ED 50 = 0.90 µM) with good water solubility. Further, molecular modeling studies confirmed the obtained biological results.

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Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling

Cited by 73 publications

References 25 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

A New Approach in Cancer Treatment: Poly(ADP-Ribose) Polymerase-1 Inhibitors

Synthesis and Evaluation of Tricyclic Derivatives Containing a Non-Aromatic Amide as Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors

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