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Squires bingham model 16 reassembly torrent

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squires bingham model 16 reassembly torrent

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C , , 25, doi: Lidon, J. Salmon — Soft Matter 10, doi: Schatz, V. Sebire, B. Pavageau, G. Wantz, L. Hirsch — Mater. Guillot, A. Colin — Microfluidics and Nanofluidics , 17, doi: Dufrechou, E. Mignard, M. Drenski, W. Reed — Macromolecular Reaction Engineering , 8, doi: Du, H. Bodiguel, C. Cottin, A. Mondain-Monval — Science , , , doi: Angly , A. Iazzolino , J. Salmon , J. Leng , S. Prathap Chandran , V. Ponsinet , A.

Le Beulze , S. Mornet , M. Cuenca, M. Chabert, M. Morvan, H. Bodiguel — Oil Gas Sci. Mascetti, F. Benevides, I. Moog, L. Rocheron, J-C. Batsale, J. Lebourdon, J. Majimel, B. Pavageau, C. Mansard, A. Colin, P. Chaudhuri, L. Bocquet — Soft Matter , 9, doi: Baron, A.

Iazzolino, K. As WEE1 is considered as one of the main gatekeepers of the G2 cell-cycle checkpoint, its inhibition is particularly effective in cells inherently presenting G1—S transition defects, typically those with deficient p53 signalling. In this context, the five pivotal kinases introduced above appear as particularly relevant targets to develop therapeutic agents able to modulate the DNA checkpoint response in cancer cells.

In parallel to ATM drug target validation, the development of ATM inhibitors has arisen these last 15 years, passing from early non-specific compounds to highly selective inhibitors that entered in pre-clinical studies Fig. Their main properties are listed in Table 1. Historically, several methylxanthine-derived drugs theophylline, pentoxifyllin and caffeine were reported to sensitize cells to radiations at low millimolar concentrations.

However, the fungal metabolite wortmannin was the first compound proposed to target ATM. This is two orders of magnitude higher than the dose required for PIKK inhibition. Therefore, the contribution of PIKK inhibition in the radiosensitizing activity remains unknown. Of note, the use of wortmannin was revisited in with a nanoparticle drug delivery approach which helped to significantly reduce its toxicity.

Caffeine was largely studied and used as radiosensitizing agent although its exact mechanism of action remains unclear. Its structure suggests that it might act at high dosage as a broad-spectrum kinase inhibitor; with probable inhibition of the phosphotransferase activity of a protein kinase involved in checkpoint signalling of DNA damaged cells.

Since caffeine and wortmannin are neither specific nor useful in vivo , new ATM inhibitors have emerged. From an initial screening, the 2-morpholinophenyl-4 H -chromenone LY was identified as a hit, and this structure was optimized over the years to yield several lead compounds Fig.

First, KU was obtained by substituting the chromenone core by a pyranone and replacing the phenyl by a thianthrene moiety. However, the pharmacokinetic parameters proved unfavourable, particularly the water solubility and the tissue distribution. This allowed its use in animals mice. KU was the first ATM specific inhibitor to show significant chemosensitization of campthotecin and irinotecan in mice xenografted with human colon cancer cells HCT and SW KU is a variant of KU which encompasses a dimethylmorpholine and a thioxanthene group in replacement of the N -methylpiperazine and thianthrene moieties of the parent compound.

Overall, the main particularity of this therapeutic agent is certainly its dual chemo- and IR-sensitization action, with submicromolar radiosensitization activity observed in glioma cells. These are probably due to the inhibition of prosurvival pathways. Interestingly, the combination of IR and KU promotes preferential killing of stem-like cells and specific sensitization to agents promoting DSB.

CP was identified in as a new ATM inhibitor by screening a library of targeted kinase inhibitors. In , Min et al. Overall, this optimized compound possesses a good pharmacological profile to be evaluated in vivo as a radiosensitizer against non-small cell lung cancers NSCLC. Indeed, neither binding assays nor activity assays on isolated kinase were reported. Therefore, the biological effects of CGK might be due to cellular off-target activities, which remain elusive to date. Moreover, its pharmacological properties have not been reported yet.

Interestingly, this compound exhibits a good bioavailability, despite its apparent compact and lipophilic structure, and an ability to cross the blood brain barrier. Detailed experimentation revealed that the molecule blocks NHEJ and HR pathways, hence causing profound radiosensitization even at low doses nM vs.

Otherwise, this compound displays a strong synergy when administered in combination with IR or temozolomide alkylating agent in most of the treated gliomas, and afforded marked tumour volume reduction. Of note, no tumour growth reductions were observed when these two compounds were administered alone.

Very recently, a new 3-quinoline carboxamide derivative structurally related to Torin2 has been described. A good oral exposure was observed in rodents. Moreover, in combination with irinotecan, significant tumour volume reductions were observed in a SW colorectal cancer xenograft model. A new cell-based high-throughput screening HTS assay for ATM inhibitors was recently developed leading to the discovery of two hits.

Among them, the most promising therapeutic agent is SJ Overall, few selective ATM inhibitors have been described yet. The most interesting compounds are probably KU and KU , developed by Kudos Pharmaceuticals, and 2 developed by AstraZeneca, for which the preclinical studies have been validated.

Thus, KU showed anticancer properties as a single agent whereas KU and 2 could be used as chemosensitizers. On the other hand, the improved version of CP compound 1 might also be interesting after in vivo validation. Following the first use of non-selective PIKK inhibitors like caffeine and wortmannin as radiosensitizers, the availability of selective ATR competitive inhibitors was desired as tools to study its exact role in the DDR. This was accompanied with the hope to promote new therapeutically usable drugs targeting this kinase.

The compounds that are reviewed herein as ATR inhibitors are represented below Fig. The first molecule proposed for ATR inhibition is the natural product schisandrin B , isolated from Fructus schisandrae , and discovered by activity screening of herbal extracts. This tricyclic molecule shares structural analogy with combretastatin A4 , a cytotoxic agent targeting the colchicine binding site of tubuline Fig.

Moreover, owing to its similarity with combretastatin A4 , it unsurprisingly acts as an anti-mitotic agent. However, the poor pharmacological properties reported in mice prevented its use for in vivo experimentation.

CDK2 inhibition was also disclosed, but chemosensitization was confirmed to be due to ATR inhibition. However, the low water solubility of this compound impedes its in vivo evaluation. VE stems from the structural optimization of a molecular hit identified by HTS. Moreover, this molecule profoundly sensitizes tumours to chemotherapeutics, notably gemcitabine and cisplatin, at low concentration 80 nM vs.

It is noteworthy that VE has no effect when used as a single agent. The pharmacological data proved very promising; moreover, in vivo this compound significantly inhibits tumour growth in pancreatic MiaPaCa-2 mice xenografts without signs of toxicity. A hit-to-lead strategy furnished the chloropyrrolopyridine 3. However, potential safety concerns were reported because of in vitro inhibition of cytochrome CYP3A4, a major monooxygenase involved in drug metabolism. Compound 3 was proposed for its use as a chemosensitizer rather than as a monotherapy.

Interestingly, a better ATR selectivity was observed in cells. Despite its low aqueous solubility, AZ20 induced, as single agent, a significant tumour volume reduction 3 fold in mice xenografted with LoVo colorectal cells. However, a time-dependent inhibition of cytochrome 3A was also reported, which led to elevated exposure in mice even at moderate doses.

Finally, AZ20 underwent further structural optimizations and eventually led to the discovery of AZD This molecule exhibits an optimized pharmacokinetic profile, and is therefore orally bioavailable and active as a chemosensitizer.

No apparent toxicity on mice was observed over the 2 week treatment. Among the molecules proposed for ATR inhibition, AZD and VE appear to be the only ones suitable for in vivo use, both being actually evaluated in phase I clinical trials. Compound 3 and AZ20 could have been good drug candidates but safety concerns about cytochromes inhibition hinder their use in vivo.

The compounds that are reviewed herein as CHK1 inhibitors are represented below Fig. UCN 7-hydroxystorausporine is a natural product belonging to the staurosporine family. The lack of selectivity of this inhibitor can by partly explained by the very high molecular rigidity of the staurosporine core. Indeed, it tightly binds the ATPase binding sites of a set of several kinases, as suggested by a co-crystallization study with CHK1.

Nevertheless, its use has always been hindered by poor pharmacokinetics, high binding to serum proteins and unfavourable toxicity profile. It is noteworthy that other staurosporines, like SB , 94 were identified although UCN remains the spearhead of this family. It entered phase I clinical trials for leukaemia in , but the study has been closed due to slow enrolment. Its combination with gemcitabine has been assessed against lymphoma, although no results are available.

Abbott laboratories developed a series of cyanopyridyl containing 1,4-dihydroindeno[1,2- c ]pyrazoles as CHK1 inhibitors. Efforts were devoted to improve its poor pharmacokinetics, 97 although 4 displayed a sufficient profile to be tested in vivo. No data in animals have been reported yet, but this compound might be used as a tool for in vivo evaluation of DNA-damaging agents in sensitized cells. Macrocyclic ureas were proposed for the selective inhibition of CHK1 by structure-based design.

Preliminary pharmacokinetic analyses showed a moderate plasma exposition. It seems that the development of this series has been discontinued as no further data were subsequently disclosed. CHIR is a potent and relatively selective quinolone-based molecule. It displays an IC 50 of 0. Nevertheless, it might target FLT3 fms related tyrosine kinase 3, regulating hematopoiesis , PDGFR platelet-derived growth factor receptor, regulating cell proliferation, cellular differentiation, cell growth and development and GSK3 glycogen synthase kinase 3, regulating cell proliferation, migration, glucose levels and apoptosis as they display IC 50 values of 5.

No activity was observed as a monotherapy but radio- and chemosensitizing effects were reported at submicromolar concentrations in MDA-MD melanoma cell lines. Indeed, the immobilisation of topoisomerase I provokes collision with the replication fork and leads to DSB. Of note, no signs of toxicity or significant body weight loss were observed in animals.

This molecule presents chemo- and radiosensitizing effects in the — nM range and an EC 50 value of 0. AZD entered phase I clinical trials, in combination with gemcitabine, a nucleoside analogue widely used as a chemotherapy agent. These studies were terminated after a full review of program data and assessment of the current risk—benefit profile.

Nevertheless, this compound remains a valuable tool for the study of DNA checkpoint biochemistry. It possesses a good toxicity profile but the pharmacokinetics proved ameliorable with a moderate distribution, a short half-life 2. In the latter case, no enhancement of systemic toxicity of gemcitabine was observed. It promotes a significant sensitization ratios: 6.

It was presented as a CHK1 antagonist but other kinases inhibition may contribute to the observed chemosensitization. An analogue of this compound, PD , has been disclosed to inhibit CHK1 but prevalently affects WEE1; therefore it will be discussed in the dedicated section vide infra.

It enhances irinotecan and gemcitabine anti-tumour activity in several colon cancer cell lines HT29, SW, and Colo; enhancement ratios: 3— The pharmacokinetics proved moderate because of high binding to plasma proteins, short half-life and high clearance. Moreover, a moderate tumour growth delay was observed in mice xenografted with SW cells. It displays a specific CHK1-dependent mechanism-of-action in cells at nM, and good microsomal stability.

Most importantly, it is the first CHK1-selective inhibitor that is orally bioavailable. However, the in vivo behaviour of CCT is not uniform. Varying levels of oral exposure and clearance are observed. It is noteworthy that CCT also acts as a single agent. In , it entered phase II clinical trials alone or in combination with gemcitabine in subjects with relapsed acute myeloid leukaemia.

It proved orally available with an acceptable pharmacological profile. Moreover, it does not increase the gemcitabine systemic toxicity, and xenograft experiments with Calu-6 lung cancer cells showed a significant reduction of CHK1 phosphorylation in the tumours. It was suggested that the anticancer property of LY might be enhanced when used in combination with an autophagy inhibitor chloroquine.

Ultimately, this compound leads to chromosome fragmentation at 33 nM concentration and replication catastrophe in vitro and in vivo. Strong nanomolar inhibition was retained in cells 9 nM, HeLa and 4-fold tumour growth inhibition was reported in Calu-6 lung cancer xenograft models. The pharmacokinetics and the in vivo efficiency of the compound remain to be evaluated.

If they are validated, it might be a promising candidate as both monotherapy and chemosensitizer of gemcitabine and irinotecan. Very few information and biological data are available on these compounds, yet. Among the biological targets reviewed herein, CHK1 is the one whose inhibition has been the most studied. The two latter are currently evaluated in phase II clinical trials. The compounds that are reviewed herein as CHK2 inhibitors are represented below Fig.

These compounds are secondary metabolites isolated from the sponges Axinella verrucosa and Acantella aurantiaca. Moreover, the chemical synthesis of this compound proved delicate at some steps, particularly for the regioselective bromination. Issued from HTS and hit-to-lead strategy, the key points of the structure are the presence of the amide and of the terminal chlorine. Indeed, the corresponding carboxylic acid without chlorine displayed an IC 50 of nM.

However, used in the low micromolar range, it remains a valuable tool to probe CHK2 inhibition. PV is a dissymmetric optimized analogue of NSC which shares the same guanylhydrazonearyl moiety. Therefore, further structural optimization of PV should be undertaken. VRX was identified by screening of a small kinase inhibitor library, followed by a hit-to-lead optimization. Moreover, neither IR, nor chemo-potentiation of doxorubicin or cisplatin cytotoxicity has been evidenced.

This also raises the question of the correlation between CHK2 direct inhibition and the observed anti-proliferative effects. Hilton et al. Subsequently, a hit-to-lead optimization afforded the aminopyrimidine 7. In this in vivo study, it showed a strongly enhanced apoptosis induction after IR exposure. CCT might be a good research tool for in vitro and in vivo pharmacological studies as well as a potential clinical candidate if in vivo studies are validated.

To conclude, only four reasonably selective CHK2 inhibitors have been described to date. CCT appears as the most promising compound, but in vivo studies are still needed. The compounds that are reviewed herein as WEE1 inhibitors are represented below Fig. The first compound that have been reported with an inhibitory activity against WEE1 is the non-selective 6-aryl-pyrido[2,3- d ]pyrimidine derivative, PD This molecule has been identified through a screening performed on a compound library, and by means of tyrosine kinase assay.

In combination, it acts as a modest p53 dependent radiosensitizer with a maximal enhancement ratio of 1. This is less than the impact of caffeine or UCN respective enhancement ratios of 2. Moreover, cell toxicity was observed from 6 h exposure; thus the therapeutic window of cellular effectiveness versus cellular toxicity of the compound is lower than the one of caffeine or UCN Attempts devoted to modify the structure to simultaneously improve both the absolute potency and selectivity towards WEE1 were unsuccessful.

Indeed, the observed activities could not be separated from an even more potent inhibition of c-Src kinase. Optimization of PD resulted in the discovery of WEE1 inhibitor II that bears two additional substituents: a butyl chain on the indole nitrogen and a chlorine atom on the phenyl ring.

Solubility problems persisted and no in cellulo activity was obtained. Importantly, these co-treatments do not significantly increase the initial toxicity of the chemotherapeutics gemcitabine or 5-fluorouracil in mice. Similar results were obtained with the combination of MK with another CHK1 inhibitor, AZD , in vitro and in vivo , in melanoma, 45 neuroblastoma and for mantle cell lymphoma, an aggressive and incurable disease characterized by a deregulated cell cycle.

Lastly, a pyrimidine-based tricyclic molecule was proposed in by AbbVie for the inhibition of WEE1. Among a series of potential WEE1 inhibitors, pyrimidopyrimidinone 8 emerged as the most promising molecule. Oral in vivo potentiation of irinotecan was evidenced in mice xenografted with H cancer cell line, rendering this compound promising for further preclinical evaluation.

Therefore, the standard drug for studying WEE1 inhibition in vitro and in vivo should be MK , which is currently evaluated in phases I and II clinical trials. Pyrimidopyrimidinone 8 is an interesting molecule in the pipeline that could reach the preclinical stage in the near future. This last decade, growing interests have been dedicated to the so-called cancer stem cells CSC hypothesis. This model supports the idea that tumours, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to differentiated tissue cells.

Indeed, stem cells have developed protection mechanisms and improved repair compared with differentiated cells. CSC employ several mechanisms to escape therapeutic assaults drug efflux activation, anti-apoptotic signalling, hypoxia management….

Nevertheless, as the great majority of anti-cancer therapies radio- and chemo-therapies rely on DNA-damaging agents, tackling the enhanced DDR appears as a particularly attractive strategy to improve their efficiencies.

Moreover, several studies suggest that CSC contribute to radio- and chemoresistance through enhanced activation of the DNA damage checkpoint response and increased DNA repair capacity. Furthermore, the CSC fraction within the tumour cell population typically increases after repeated cycles of DNA-damaging treatments that preferentially kill the non-stem cells. As a result, classical therapies become progressively ineffective towards these CSC-enriched tumours.

This re-sensitization might provide useful therapeutic models for malignant cancers. Several reports point out the interest of tackling CHK1 in the specific context of the CSC, 90 , — while, to the best of our knowledge, no examples of specific CHK2 inhibitors have been studied in CSC models so far. Apart from a study of WEE1-related radiosensitization in glioblastoma neurospheres, very few reports on WEE1 inhibition in the particular case of cancer stem cells have been published.

These inhibitors are presented in Table 6 and discussed afterwards. We also introduce a set of suggestions for the use and the development of new compounds to study cell cycle arrest, to induce a mitotic catastrophe and cell death in CSC. In , the first attempts to sensitize CSC were undertaken using caffeine in combination with etoposide. However, this potential is tarnished by the fact that caffeine also induced by itself a reversible growth arrest that is associated with increased fraction of CSC.

The remaining cells lose their tumorigenicity either in vitro or in vivo. The authors imply that this higher sensitivity might be due to lower ATM intracellular levels and DNA repair capacity in BCSC, which constitutes a controversy relative to most other reports. On the other hand, Carruthers et al.

Additionally, an enhanced apoptotic rate, relative to the untreated cells, was observed. Contradictory, Raso et al. The correlation between these two events has not been fully deciphered yet.

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Me shooting the Squires Bingham Model Gary shooting the M in 22 cal. This rifle is super fun to shoot and wont break your bank. Let us know what you think about it And today I'm gonna show you my Squire Pinkham model 20 bucks so I knew have eight in the makers eight shut mag twenty long Today we disassemble and assemble our Savage. Not without issues. Thanks for watching. Squires Bingham model 15 22 mag. First groups at the range Armscor K-mart Kassnar importers.

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Rock Island Armory M Disassembly. Originally Posted by ran I was ranged at 50 yards and hitting raw eggs, cans, potatos, whatever i shot at, it has awsome rifling too. I was surprized how nice it shoots actually. Only a dry powder graphite is suggested. Great job on the gun. I know this is an old thread but here is hoping you still have notifications turned on for updates.

I am going through the same process with the same gun only mine is not as bad as your starting point. Couple questions if you can shed some light. How did you get the trigger assembly off of the receiver. I have removed the front screw no problem but something else is still holding it on right under the trigger. Because of the springs and screws for the safety I'm trying not to be to explorative and would rather some guidance than vacuuming up small parts.

Also did you ever separate the barrel from the receiver? I like to re-blue metal personally but don't like to do barrels still on the receiver. I have tried a bit of force and mallet but she won't budge. It is just sitting now with some solvent. Any clues would be appreciated. Hi phishisgroovin, Good Day, I Have an armscor retractable airgun, need to know how you've dismantle the two 2 extension Rod housing and Butt Block extension rods.

Can you guide me on how to dismantle it. Just learn and already dismantled already the Extension Rod housing. All rights reserved. Add Thread to del. Wong this Thread! User Name. Remember Me? Mark Forums Read. Thread Tools. Quote: Originally Posted by 1shot Awesome Quote: Originally Posted by redtazdog Does this gun use the Bingham mags like this? Quote: Originally Posted by reppinthe so did we ever hear how this thing shot?

Quote: Originally Posted by ran this rifle shoots really nice actually! LinkBack URL. About LinkBacks. Digg this Thread! Bookmark in Technorati.

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