Gordon Stein, CFO of CleanTech Lithium, explains why CTL acquired the 23 Laguna Verde licenses. Watch the video here.
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Good post citizen79 interesting read.
Regards
SOG
Hi T2. apologies late getting back as been on nightshift this week. As far as I am aware kinase inhibitors work best in pairs. As I understand it the type of kinase inhibitor is around how it works and inhibits which signals. Having a Tyk2 inhibitor does not mean it can inhibit IL-6 and I will use the word effectively. I will wake fully have a cuppa and look into some more. I would find it odd that we are the only TYk2 inhibitor (albeit with Jak1) that affords effective inhibition of IL-6. It maybe that one or more of our patented molecules have nailed it, but cannot support that with any evidence, The deeper you look into it the more complex it becomes. I have attached below some early research. Paragraph 3 interesting.
The Janus kinase (JAK)1family of non-receptor tyrosine kinases consists of four mammalian proteins (Tyk2, JAK1, JAK2, and JAK3) that play a critical role in initiating signalling cascades of a large number of cytokine receptors .
All JAK proteins possess a carboxyl-terminal tyrosine kinase (TK) catalytic domain, a central kinase-like (KL) domain, and a large amino-terminal (N) region, which has been subdivided into five JAK homology regions (JH7 to JH3) based on sequence conservation (3). The specific and noncovalent association of these kinases to the intracellular region of cytokine receptors governs their activation upon ligand binding .
' We are interested in understanding the mode of action and specific roles of Tyk2, which is activated, together with another JAK family member, by the type I interferons (IFN) (several a and one ß subtypes), by interleukin (IL) 6, IL-10, and IL-12 .'
The IFN-a/ß receptor is present at low numbers on the surface of all cell types and consists of two transmembrane proteins called IFNAR1 and IFNAR2 . The IFNAR2 gene generates several alternatively spliced forms, but only the product harbouring a long intracytoplasmic domain (IFNAR2c) is part of a functional IFN-a/ß receptor (12). Whereas the stoichiometry and spatial organization of these components within the receptor complex are unknown, the epitopes on the IFN molecule contacting IFNAR1 and IFNAR2 are being identified . High affinity binding of IFN-a/ß to the receptor results in tyrosine phosphorylation and enzymatic activation of the associated JAK1 and Tyk2 in a defined temporal order, which is thought to result from the topology of each kinase within the complex . Studies of kinase-deficient mutant cell lines showed that in the absence of either kinase, high affinity IFN-a binding is impaired, demonstrating a structural role of these enzymes in the formation of functional receptors. Our recent in vivo studies of deleted forms of Tyk2 expressed in Tyk2-deficient 11,1 cells have highlighted distinct functions of the protein toward the expression and the binding activity of the receptor complex. Each function appears to be contributed by a different domain adding more complexity to the receptor-kinase complex.
Good morning Ahfam. Our Tyk2 Jak1 inhibitors look to have so much scope it is difficult to predict at which targets they will aim at first.
If it is true that no other company investigating Tyk2 inhibits IL-6 as Thoth suspects and Dr Reader has patented it then we are in for a moonshot £ land within 2 days of secret patent details release, institution TR1's left, right and centre.
Exciting times ahead- Many happy returns chaps
Thoth, this is exactly what has pricked my ears so to speak lately;
Below is a comprehensive link on IL-6 which you've no doubt seen, so apologies in advance, but others on the board might like to have a read:
Translating IL-6 biology into effective treatments:
https://www.nature.com/articles/s41584-020-0419-z
ATB
Thoth - this was published last year, no idea if it helps your research or not but it does mention il-6.
https://www.nature.com/articles/s41418-020-00621-x
An extract -
"TYK2 promotes the production of pro-inflammatory cytokines during endotoxemia
We next assessed systemic cytokine levels in WT, Tyk2K923E and Tyk2-/- mice at 2, 6 and 16?h after LPS injection. IL-6, TNFa and IL-1ß levels were comparable in mice of all genotypes at 2?h after LPS challenge (Fig. 2a), confirming that immediate early pro-inflammatory responses do not depend on TYK2 [13, 14]. Against our expectations, IL-6, TNFa, IL-1ß and IL-18, which was first detectable at 6?h after treatment, were strongly reduced in Tyk2-mutant mice at 6 and 16?h after LPS treatment (Fig. 2b, c). In line with reports on Tyk2-/- mice [12, 14], Tyk2K923E mice failed to produce IFN? and had strongly reduced systemic IL-27 levels (Supplementary Fig. 3a, b). Moreover, Tyk2K923E and Tyk2-/- mice failed to produce IL-17A (Supplementary Fig. 3a, b), extending the reports on the importance of TYK2 for IL-17A production [2, 3, 28,29,30,31,32] to LPS-induced endotoxemia."
Regards,
Hotblack.
sad old git. I actually havent found any refrence to il-6 in any other tyk2 inhiitor. may be marketing, or we may be unique in this key pathway
Common now enough already- it was only a 4m holding, some on here have much more esp. the HNWI's and they aren't selling. The person probably needed the money and needed to sell as nothing in the science has changed.
And besides soon we will see buys and sells in much larger quantity as we get the expected newsflow.
We soaked up a 4m sale and closed the day 3% lower, it really isn't that scary.
I'd say we know our Tyk2 is game as the US Army research has already vouched for it in Lupus and potentially other illnesses-
From the US Army research update 24 July 2020 RNS-
The authors concluded that an approach using selective TYK2/JAK1 inhibitors may lead to the development of a therapy for lupus that does not involve the harmful side effects of systemic immune system suppression and may benefit numerous lupus patients in need of new options. They also noted that the results could influence treatments of other autoimmune diseases such as arthritis and psoriasis.
Specifically, it was reported that treatment with TYK2/JAK1 inhibitor SAR-20351 (now known as SDC-1802) reduces autoantibodies (biological markers of lupus severity) in a spontaneous mouse model of SLE. The data also provided evidence that SAR-20351 inhibits cytokines that play a critical role in lupus, including interferon-alpha, IL-6 and IL-23. The inhibition of IL-23 signalling by SAR-20351 may play a role in the decrease of autoantibodies in the lupus mouse model, as IL-23 signalling drives the differentiation of Th17 cells, which leads to autoantibody production and are pathogenic in lupus.
The Tyk 2 Deucravacitinib ( Tyk 2 only and an allosteric inhibitor)) has a good safety profile which is extremely encouraging as Tyk2 on its own, This does contradict with Tyk 2 having known side effects and reinforces its safety profile as a viable form of treatment.
Note a salient point from the Deucravacitinib report. ' TYK2 is an intracellular signaling kinase that mediates signaling of IL-23, IL-12 and Type I IFN, which are naturally occurring cytokines involved in inflammatory and immune responses.
Our Tyk2 ( SDC 1801) is 'contrary to reports in TYK2-/- mice, signalling by a wide variety of cytokines was found to be impaired thus highlighting non-redundant roles for human TYK2 in the function of Type I IFNs, IL-6, IL-10, IL-12 and IL- 23.'
Note we have IL-6 and IL-10 in addition to type 1 interferons, IL-12 IL-23 and IL-12. In addition we are non allosteric.
I am not going to say here that one of these inhibitors is far superior to the others. what I will say however as these new generation of Tyk2 inhibitors come through, they are showing a much improved efficiency at treating targeted diseases
and without doubt showing a far greater safety profile. First generation JAK inhibitors need replacing badly.
Well done BMS for this additional and safer treatment, in this instant for treating patients with moderate to severe plaque psoriasis. However, I will add and interesting to note that no information with regards as suitable, or to be more precise, investigation the use of against Covid 19. Nothing to indicate IL-6 and IL-10. I would doubt Deucravacitinib would prove effective in treatment of Covid 19 as would have already been investigated ( as after all recommended by WHO to use Tyk2 inhibitors). This would also indicate a shortfall in treating other serious lung infections too such as pneumonia.
All in all looking very very favourable for our SDC1801 Tyk2 (with an optimal amount of Jak1 according to TM).
Regards
Thoth the safety data and efficacy from bms TYK2 Deucravacitinib looks good.
https://news.bms.com/news/details/2021/Bristol-Myers-Squibb-Presents-Positive-Data-from-Two-Pivotal-Phase-3-Psoriasis-Studies-Demonstrating-Superiority-of-Deucravacitinib-Compared-to-Placebo-and-Otezla-apremilast/default.aspx
We'll have to wait until Q1 2022 for our own phase 1 safety profile.
4.4m is a large sell (if it really was a sell but let's not go there) that would explain the drop today but if it's a stale bull or whoever the good news is they are likely gone for good ... Great levels to top up if you have the funds ... Expect a bounce tomorrow methinks ... Have a good rest everyone tomorrow is another day ... Hugs etc Mafuta
Potnak. Entirely agree. A market is a market and i think we have lost several lths on the way. Replaced by new ones.
Valuations are very tricky. At the bottom end neuvolution c 3p a share. Top end otezla c £5 a share (approved in 50 markets but only in one indication. Psoriasis). If covid lands 20 quid upwards. But its very very hard to judge where to get off. Im watching bms tyk2 data very closely. And if azn ir j&j make a move on 737. All in but monitoring very closely indeed.
If they bought at 0.6p which wasn't that long ago. They just sold a 10 bagger. Not a bad bit of work. We're all here to make money and a profit is a profit is a profit. There will be lots of selling at 10, 12, 15, 20p or more and I can imagine 28p will be a hard nut to crack :-). Its a market, some buy, some sell. One can't happen without the other.
Batonrouge totally agree I sold mine in batches just to clear/recover my investment over the years since 2009 and still believe in the rest of my holding will at least get me to the 10p party - my selling didn’t batter the eyelid of any of the HNWI’s who subsequently invested - sometimes an investor makes a decision that doesn’t concur with your own just DYOR
GLA
It's only 1 investor and could have been for any number of good reasons.
I sold 4m the other month that gave back my investment and now have a free ride with a pretty reasonable holding so can mean anything- all I would say is someones’s buying them as Julie1 stated in her mad 5 minutes and finished north!
@ Julie hope all well with you too!
GLA
Plenty of 500k buys to take its place. :-)
adfvn says 14,908,497 today.
seems like an interesting figure.
would welcome any perspectives.
Maybe I am being thick here (not for the first time) , but LSE is showing a volume of 1,849,764 as being sold for the day......how does that compute when there is a 4.4m sell on record ????
Was going to ask about the 3x 500,000 that were showing as unknown earlier but that 4.4m sell has blown that
Hope they’ve made a good profit
GLALTHs
That's a massive sell up :(
Just appeared. That explains the drop today. Still holding on to my nuggets extra tight