Member Info for Fadec92

The report is $4200 and looks very questionable and cheap, using some big terminology what the hell is “data triangulation which involves data mining“ think you’ll have more fun paying for the full Publication of T.Sen’s Journal Combination treatment of the oral CHK1 inhibitor,l enhances the effect of PD-L1 blockade by modulating the immune microenvironment in small cell lung cancer, It’s $4170 dollars cheaper and probably give you better info!

Ah it’s below the mid point of the spread though 0.38,0.39 / 0.40,0.41 so below the mid point which is was 0.395!

Best way would be :-

“please someone own up to the 10.5k to say if it was a buy or sell put my mind at rest”

Actually can’t tell as it’s exact to the mid point of the below trade! :/)

I think it’s a sell as spread was 0.37 - 0.41 from the trade £1990 before at 08:13:38

Is that a political pledge to fund Cancer Research Thoth, and do you think London visit will be more than just Mome, I know an America investor is flighting over to ask Nick some awkward questions about the DDR assets while in London!

CFP I’m in agreement and I think it was a positive move 2-3 months back when a couple of LTH said we need more info and scribed an email, accountability is good and shows we not going to be pushovers and for them to focus more with the job at hand and we know our position corporate wise with us together having a good deal of shares together as Thoth said!

Looking at the sells over last couple of sessions I think it’s investors who understand tech charts as the 8ema was broken and come out of a downtrend that was in play from August, it’s been hugging a positive short term rise with the lows getting slightly higher each phase since August!

https://imgur.com/a/QfWE9Sd

A Dual Inhibition, a Better Solution: Development of a JAK1/TYK2 inhibitor

“In summary, 6 represents a promising addition to the armory of JAK enzyme inhibitors for clinical evaluation. Its selectivity profile, together with its good oral bioavailability, allows definitive testing of the clinical hypothesis that a dual inhibition of JAK1 and TYK2 can lead to a clinical benefit at a well-tolerated dosing regimen. In a more recent paper,12 the phase 1 study results indicate that the TYK2/JAK1 inhibitor 6 has a favorable safety profile and is well tolerated at single doses up to 200 mg and multiple doses up to 175 mg once daily in healthy subjects and up to 100 mg once daily in patients with plaque psoriasis, respectively. The obtained results suggest that treatment with 6 leads to a clinical benefit as measured by PASI scores in patients with plaque psoriasis, supporting further clinical development of 6 in the treatment of psoriasis and other inflammatory diseases.”

https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b01397

Stoney I’ve never seen anything untoward here compared to other places I think they are doing what they said in RNS yes I agree it’s been a long time but com’on these guys are putting together cutting egde cancer compounds and are not rolling out rubbish with 10 years with 2 persons work (more John than Tim happy to be proved wrong), you look at the work involved with getting pre-clinical done after molecule selection with how low the costs are (compared with big companies and big budgets) com’s are non-existent I know don’t really care and is telling in a way that they don’t need us and don’t care either and you either decide to do your research on the company or you listen to what peeps say taking too long or can’t do a deal i don’t share most has said before I remain in excited isolation!

I think the last guy is speaking for the srra investment communities! Lol..

https://imgur.com/a/TMlHFYn

https://imgur.com/a/RmDxJv0

Aber they have the only specific TYK2’s for selectively!

https://www.businesswire.com/news/home/20191115005499/en/Bristol-Myers-Squibb-Receives-Clearance-U.S.-Federal-Trade

RMM it does sound too me that they are trying to satisfy the market rules to still list on the Nasdaq!

“There is a stigma attached to doing a reverse stock split, as it underscores the fact that shares have declined in value, so it is not common and may take a shareholder or board meeting for consent. Many institutional investors and mutual funds, for example, have rules against purchasing a stock whose price is below some minimum, perhaps US$5.[citation needed] A common reason for a reverse stock split is to satisfy a stock exchange's minimum share price.”

https://en.m.wikipedia.org/wiki/Reverse_stock_split

Before the statement they didn’t have the money, they have now and will want to increase their shareprice to retain Nasdaq status and the progress of SRA737 was the one that was shaping their MC and I’m sure a positive plan to take SRA737 forward with a partner would do it justice!

RMM “Sierra show no appetite for progression” is a common negotiating trate in bargaining when wanting to get something for better terms!

Was just going to say if you were to buy do it in small amounts as would push the price up!

I think they have to give 61 days notice of share increase/decrease will take 10% and can go up to 20% on the preferred A stock is that right, probably some here will understand the contract better!

AJthoth and SDC-1802 is only in class, novel, there is another TYK2 for T-ALL Nimbus Therapeutics NDI-031301 like John Readers original SAR20347 in the publication I posted but not for solid tumors!

The Publication is a couple of days old and shows they are definitely in the right place, John R has been developing Tyk2 for long time.

TYK2: An Upstream Kinase of STATs in Cancer

The biological relevance for TYK2-dependent cytokines activating STAT3 is best established for the IL-10R2 utilizing IL-22 and the IL-12Rß1-utilizing IL-12 and IL-23. IL-22 is a central cytokine in tissue-barrier function, wound healing, and epithelial homeostasis and repair. Cancer promoting, as well as restraining, functions were described. IL-23 is a key mediator of inflammation, bridges innate and adaptive immune responses, and is known to support tumorigenesis and metastasis. IL-12 is central in promoting cell-mediated immunity to infection and cancer. However, this anti-carcinogenic function can be counteracted by IL-12-STAT3-promoted production of pro-carcinogenic IL-23.

https://www.mdpi.com/2072-6694/11/11/1728/htm

Full PDF Publication!

https://res.mdpi.com/d_attachment/cancers/cancers-11-01728/article_deploy/cancers-11-01728.pdf

Sareum’s Poster

“It has been reported that STAT3 signalling in both the tumor, and microenvironment, is critical in shifting the balance from IL-12, a central cytokine in antitumor and antiviral immunity, to potentially pro-carcinogenic IL-23 production.“

C086 - Immunotherapeutic effects of the TYK2 inhibitor SAR-20351 in syngeneic tumor models.

Background: TYK2 (tyrosine kinase 2) is a member of the Janus family of non-receptor tyrosine kinases and has been shown to play an important role in the signalling of type I interferons, as well as IL-12 and IL-23, via phosphorylation of downstream STATs. The TYK2/STAT1/BCL-2 pathway is implicated in the survival of leukemic cells in a proportion of T-ALL cases. It has been reported that STAT3 signalling in both the tumor, and microenvironment, is critical in shifting the balance from IL-12, a central cytokine in antitumor and antiviral immunity, to potentially pro-carcinogenic IL-23 production. Furthermore there is increasing evidence that chronic tumor interferon signalling leads to multigenic T cell exhaustion and resistance to immune checkpoint blockade. Additionally, TYK2 has been suggested to play a key role in CTLA-4 STAT3 signal transduction in B cell lymphomas and in melanoma associated B cells. We have previously reported on SAR-20347, a 1,3-oxazole-4 carboxamide, which is an orally bioavailable potent and selective inhibitor of TYK2, which causes tumor regression in in vivo models of T-ALL, and which has shown striking reductions in STAT phosphorylation downstream of IFNa signalling, and IFN? production in response to IL-12 both in vitro and in vivo. Here we report the effects of SAR-20351, an orally bioavailable optimised analog of SAR-20347, on tumor cell viability and components of the tumor microenvironment in immunocompetent mouse models.

If Synthetic Lethality compounds are needed for Replication Stress then there’s only these 2!

“ATR and CHK1 proteins are critical in the response to replication stress”

AstraZeneca has the ATR and Sierra has the CHK1, so just these two for RS!

Emerging DNA Damage Signaling Inhibitors

The DDR pathway is governed by kinases such as ATR, ATM, CHK1, and CHK2. Furthermore, proteins such as WEE1 and CDC7 govern replication firing and hence are key to controlling replication stress in cancer. Although ATM inhibitors and CHK2 inhibitors were the first to be developed, it is ATR inhibitors, and also CHK1 inhibitors, that have progressed the furthest in clinical development, as detailed above and in recent reviews. Whereas ATM and CHK2 proteins are important in the response to DNA double-strand breaks, ATR and CHK1 proteins are critical in the response to replication stress. Replication stress may be described simply as an obstructed replication fork, either by dNTP deprivation or physical obstruction, which continues to unwind the double-stranded DNA (by helicases) but fails to synthesize the DNA, resulting in long stretches of single-stranded DNA. These single-stranded DNA regions signal replication stress through ATR and are protected by RPA. Severe or persisting replication stress may result in replication fork collapse, breakage of the DNA, and cell death. A major breakthrough was the discovery that oncogenes not only provide proliferation signals but also generally cause replication stress that activates the ATM-p53 tumor barrier. It is likely that the underlying replication stress commonly observed in cancer is also providing the therapeutic index for killing cancer cells versus causing adverse effects to nonmalignant proliferating cells.

The underlying principal strategy with ATR, CHK1, and WEE1 inhibitors is to prevent cancer cells from surviving under increased replication stress conditions. Hence, combining DNA-damaging agents, such as cisplatin or gemcitabine, synergizes efficiently with ATR and CHK1 inhibitors. Interestingly, although the mechanistic underpinnings are unknown, CHK1 inhibitors have been found to synergize particularly well with gemcitabine, whereas ATR inhibitors combine relatively well with cisplatin. There is still much to be discovered about the exact lesions formed and how these are differentially signaled.

https://ascopubs.org/doi/10.1200/EDBK_238473

List of DDR Compounds in Development but as you can see some are now dis-continued!

https://oncologypro.esmo.org/Oncology-in-Practice/Anti-Cancer-Agents-and-Biological-Therapy/PARP-inhibition-and-DNA-Damage-Response-DDR/DNA-Damage-Response/DDR-in-Cancer/DDR-Compounds-in-Development