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1.
robust small molecule-aided cardiac reprogramming systems selective to cardiac fibroblasts:
https://www.sciencedirect.com/science/article/pii/s2589004223025439
"combining alk5 and jaks/tyk2 inhibitors (2c) greatly improves cardiac reprogramming"
a couple of links for the non-readers:
2.
jak1 tyk2 in ra
https://www.youtube.com/watch?v=thkcnczwxgk
3. finding the right pathway in psoriasis: tyk2 as a therapeutic target in real-world practice:
https://www.youtube.com/watch?v=qufsa4omzs0&pp=yguedhlrmg%3d%3d
4. jak-stat signaling in inflammation and stress-related diseases: implications for therapeutic interventions:
https://link.springer.com/article/10.1186/s43556-023-00151-1#sec33
"in conclusion, the importance of the jak-stat pathway in stress-related disorders transcends academic speculation. the emergence of isoform-specific inhibitors, combination therapies, and precision drug delivery systems not only enriches our therapeutic ****nal but also adds nuance to our understanding of the role of the jak-stat pathway in the complex matrix of stress and inflammation. the extension of jak-stat inhibitors from their origins in classical immunology to their emerging role in stress-associated disorders marks a substantial shift, thus expanding both our theoretical understanding and the scope of potential therapeutic interventions."
heavy science for those who revel in it :)
5. community analysis of large-scale molecular dynamics simulations elucidated dynamics-driven allostery in tyrosine kinase 2:
https://onlinelibrary.wiley.com/doi/full/10.1002/prot.26631
atb beer o'clock
Apologies if posted previously,
SRA737 - :)
November 2023
Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer:
https://www.researchgate.net/publication/375512557_Synthetic_lethal_combination_of_CHK1_and_WEE1_inhibition_for_treatment_of_castration-resistant_prostate_cancer
"Abstract
WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC/NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737
exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage."
In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC."
&
"In summary, our study identifed WEE1 and CHK1, two critical CCR and G2/M checkpoint regulators, as potential novel therapeutic targets for CRPC. We further demonstrated the efficacy and tolerability of the WEE1 inhibitor AZD1775 and CHK1 inhibitor SRA737 as single agents and in combination for CRPC/NEPC treatment in a transgenic mouse model of advanced prostate cancer. Our findings provide solid preclinical support for the further evaluation of these agents for the treatment of lethal prostate cancer."
ATB
1. Bit of a buzz around TLL-018, several tweets:
https://twitter.com/drdavidliew/status/1723874952665764160
"TLL-018, the dual JAK1/Tyk2 inhibitor which caused all the chatter at #EULAR2023, now with more full data showing it absolutely smash tofacitinib in RA, with similar safety.
"This is a spectacular compound - unbelievably spectacular” - Roy Fleischmann
#ACR23 ABST0840 @RheumNow"
& 2nd Tweet:
https://twitter.com/drdavidliew/status/1723876296093225034
"More on TLL-018
How?
A: Everyone surprised. But maybe dual mech benefits re: pain via IFN
Where’s the multinational RCT in RA?
A: Priority on rapid registration in China, quickly. But ph2 trials for psoriasis happening in US, results so far look consistent."
2. Another TYK2 Ticks the Boxes:
https://www.youtube.com/watch?v=rqovM6NPKfk
Nov 12, 2023 - Dr. Janet Pope discusses late-breaking abstract L12 presented at the 2023 Convergence meeting in San Diego, CA.
3. Cytokine Profile in Lung Cancer Patients: Anti-Tumor and Oncogenic Cytokines :
https://www.mdpi.com/2072-6694/15/22/5383
4. CALCRL induces resistance to daunorubicin in acute myeloid leukemia cells through upregulation of XRCC5/TYK2/JAK1 pathway:
https://journals.lww.com/anti-cancerdrugs/abstract/9900/calcrl_induces_resistance_to_daunorubicin_in_acute.222.aspx
ATB
Good morning Augustdestiny, I hope you are well & thank you for your kind words.
I’ve been away with my family soaking up the sun in warmer climes. Sadly, now back with the tan fading fast!
I am still fully invested, and while mildly frustrated with the current share price I remain here for the long-haul. The science has in no way failed and I am very pleased with the pace things are moving in Oz. This combined with continued validation in the TYK2i/JAK1i and indeed CHK1i spaces are what keep me here.
I continue to research & dig deep into the science as that (IMO) is the foundation of everything Sareum and indeed our competitors are trying to achieve - I have seen nothing to date in the science to worry me about my investment here.
I am more than happy to admit company financing is not my specialist subject and I therefore have to trust the BOD in relation to the RF position, HNWI’s & future funding etc. I invest I Sareum, I therefore invest in them.
If I didn’t trust them, I would be off in a flash.
Time will tell if my faith in the BOD & the science is correct.
As a side note, I have more people filtered here than you could shake-a-stick-at and the state of calm I retain because of this is something I would wholeheartedly recommend to others:
One simply doesn’t need to read the repetitive inane drivel & actually allowing oneself to be exposed to it, when tools are there to effortlessly block it, is an utter waste of energy IMO.
ATVB, A very relaxed, LTH (Who continues to pick up what he regards as cheap shares at every opportunity)
PS. SDC1802 will be the biggie, once SDC1801 is validated of course! Cheeky link for the science folks;)
09.11.2023 - New perspectives in cancer immunotherapy: targeting IL-6 cytokine family:
https://jitc.bmj.com/content/11/11/e007530
direct .pdf: https://jitc.bmj.com/content/jitc/11/11/e007530.full.pdf
1. Alumis prepares/patents & tests new TYK2 inhibitors: - They mention using against cancer once or twice ;)
https://worldwide.espacenet.com/patent/search/family/085979760/publication/WO2023178234A1?q=pn%3DWO2023178234A1
https://worldwide.espacenet.com/patent/search/family/086142785/publication/WO2023192351A1?q=pn%3DWO2023192351A1
https://www.alumis.com/pipeline/
2. Sotyktu (deucravacitinib) Long-Term Data Demonstrate Durable Efficacy and Consistent Safety for up to Three Years in Moderate-to-Severe Plaque Psoriasis:
https://news.bms.com/news/corporate-financial/2023/Sotyktu-deucravacitinib-Long-Term-Data-Demonstrate-Durable-Efficacy-and-Consistent-Safety-for-up-to-Three-Years-in-Moderate-to-Severe-Plaque-Psoriasis/default.aspx
3. Discovery of WD-890: A novel allosteric TYK2 inhibitor for the treatment of multiple autoimmune diseases :
https://pubmed.ncbi.nlm.nih.gov/37778274/
https://www.sciencedirect.com/science/article/pii/S0753332223014099?via%3Dihub
4. New Phase 3 Data on Long-Term Efficacy of Upadacitinib in Atopic Dermatitis Presented at EADV:
https://www.dermatologytimes.com/view/new-phase-3-data-on-long-term-efficacy-of-upadacitinib-in-atopic-dermatitis-presented-at-eadv
5. Incyte Announces Positive 52-Week Data from Phase 2b Study Evaluating Povorcitinib (INCB54707) in Patients with Extensive Nonsegmental Vitiligo:
https://www.biospace.com/article/releases/incyte-announces-positive-52-week-data-from-phase-2b-study-evaluating-povorcitinib-incb54707-in-patients-with-extensive-nonsegmental-vitiligo/
6. Unveiling Abrocitinib: A Thorough Examination of the 2022 USFDA-Approved Treatment for Atopic Dermatitis (AD):
https://www.sciencedirect.com/science/article/pii/S2590098623000118#s0080
As for Sareum, steady as she goes.
ATB
Apologies for the data heavy links but this is too interesting not to share:
Plasma proteomic associations with genetics and health in the UK Biobank:
https://www.nature.com/articles/s41586-023-06592-6#Sec18
Interactive web portal
To facilitate interactive queries, visualizations and bulk downloads of summary statistics for pQTL results, we created an interactive web portal, which is accessible at:
https://metabolomips.org/ukbbpgwas/
https://www.pharmatimes.com/news/astrazeneca_reveals_new_research_to_improve_drug_discovery_1501589
https://investors.olink.com/news-releases/news-release-details/landmark-studies-utilizing-olinkr-explore-technology-signal-new
Over and out.
......and there's more (in a Jimmy Cricket voice), - for the science heads :)
5. Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544547/
direct .pdf: https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-023-01240-y.pdf
"As discussed in this article, JAK/STAT signaling pathway and its related cytokines are substantial for host defense against viral pathogens. However, in some viral diseases, they might exert pro-viral effects, leading to the progression of the disease. Novel research has resulted in fundamental updates in our knowledge of the cross-talk between this cascade and immune and antiviral responses. Despite these advancements, there are still substantial questions on determining factors in the switch between pro- and antiviral functions of the JAK/STAT and the exact mechanism through which viruses exploit this cascade for their gene replication and pathogenesis. Also, certain challenges remain about the potential of JAK inhibitors as antiviral agents, including the types of viral diseases that could be treated with the JAK/STAT inhibitors. Furthermore, the administration of JAK inhibitors has been associated with some complications, such as immune suppression. Therefore, further preclinical and clinical research is needed to comprehensively examine the specific antiviral or pro-viral activities of JAK/STAT components in each viral infection. Another existing challenge is to determine the efficient dose of JAK/STAT inhibitors for different acute and chronic viral diseases.
2. Sun Pharma Announces US FDA Filing Acceptance of New Drug Application (NDA) For Deuruxolitinib
https://sunpharma.com/wp-content/uploads/2023/10/Sun-Pharma-Announces-US-FDA-Filing-Acceptance-for-Deuruxolitnib.pdf
"U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for deuruxolitinib, an investigational oral selective inhibitor of Janus kinases JAK1 and JAK2, for the treatment of adults with moderate to severe alopecia areata. In the NDA, Sun Pharma has submitted 8mg twice daily regimen of deuruxolitinib for FDA review"
Now after all that, time for a stroll.
Good weekend all.
ATB
Morning all, Several links for those who like 'em :)
A decent & recent paper (IMO), keep an eye on those cytokines, as eluded to I think, by SOG, (apologies if not) there remains a slim possibility of SDC1801/2 in combo with CCT245737....
1. Systems Biology and Cytokines Potential Role in Lung Cancer Immunotherapy Targeting Autophagic Axis:
https://www.mdpi.com/2227-9059/11/10/2706
"Lung cancer accounts for the highest number of deaths among men and women worldwide. Although extensive therapies, either alone or in conjunction with some specific drugs, continue to be the principal regimen for evolving lung cancer, significant improvements are still needed to understand the inherent biology behind progressive inflammation and its detection."
"Therefore, to sum up the above statements, we can conclude the importance of the IL6-IL17-IL23 signaling axis in initiating innate autophagic mechanisms. And it also suggests the role of these cytokines in mediating inflammasome assembly in a cancerous state. Hence, to achieve a novel therapeutic strategy, targeting the immune signaling axis would help overcome cancer development and improve disease outcome."
2. Specificity and promiscuity of JAK recruitment regulates pleiotropy of cytokine-receptor signaling:
https://www.biorxiv.org/content/10.1101/2023.10.04.560821v1
direct .pdf: https://www.biorxiv.org/content/biorxiv/early/2023/10/04/2023.10.04.560821.full.pdf
"Our findings open new perspectives for future research in cytokine receptor signaling and therapeutic interventions. JAK inhibitors are currently emerging as important drugs for diverseconditions, but the promiscuity of JAK recruitment is currently not being considered. Thus,the TYK2 inhibitor deucravacitinib will attenuate signaling of IFN-I and other cytokines in a much more cell-type specific manner than currently appreciated. Our findings substantiate that the combinatorial assembly of JAK kinases with cytokine receptor chains enables tailored signaling responses. This may allow the innate immune system to mount responses proportional to the severity of pathogens and stimuli encountered. Future work should explore whether dysregulated JAK-receptor promiscuity underlies aberrant cytokine signaling in autoimmunity and immunodeficiency. Elucidating the molecular grammar underlying differential JAK usage promises to uncover new therapeutic strategies for immunomodulation.
3. Something or nothing, but insider sells at Ventyx along with a nervous looking share chart.... their lead asset.... VTX958 a TYK2i
https://www.marketscreener.com/quote/stock/VENTYX-BIOSCIENCES-INC-128506325/news/Ventyx-Biosciences-Insider-Sold-Shares-Worth-299-933-According-to-a-Recent-SEC-Filing-44992534/
4. A few finance folks are predicting decent return potential in Acrivon.... what is their lead asset.... CHK1/2 inhibitor....
https://www.nasdaq.com/market-activity/stocks/acrv/news-headlines
ATB
1. Atomwise Announces Nomination of its First AI-Driven Development Candidate Focused on TYK2 Inhibition and Appoints Neely Mozaffarian, MD, PhD as Chief Medical Officer:
https://www.businesswire.com/news/home/20230927754050/en/Atomwise-Announces-Nomination-of-its-First-AI-Driven-Development-Candidate-Focused-on-TYK2-Inhibition-and-Appoints-Neely-Mozaffarian-MD-PhD-as-Chief-Medical-Officer
2. Epstein-Barr virus infection: the micro and macro worlds:
https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02187-9
3. Interesting to note Roivant advertising (I mean listed) on wikipedia as of September:
https://en.wikipedia.org/wiki/Roivant_Sciences
Heres to some increased newsflow direct from Sareum in the coming weeks.
ATB
Morning,
1. Novel JAK inhibitors under investigation for systemic lupus erythematosus: - where are we now?
https://www.tandfonline.com/doi/full/10.1080/13543784.2023.2264172
Certainly worth posting the below .pdf link of the US Government funded study into SAR20347/20351 & Lupus from the DTIC back in 2019. - Apologies to LTH's already up to speed regards this, but a revisit of the text is no bad thing IMO. (I had forgotten the specific comments made regarding psoriasis & arthritis for example.)
https://apps.dtic.mil/sti/pdfs/AD1087498.pdf
2. The below is a another timely & decent read IMO - some here will enjoy this, specifically the section "So Where Do the Billions in Costs Come In?"
How Effective Is Big Pharma Internal R&D And How To Boost It?
https://www.forbes.com/sites/alexzhavoronkov/2023/09/27/how-effective-is-big-pharma-internal-rd-and-how-to-boost-it/
Certainly whets the appetite !
ATB
Good evening SOG, I thought the same yesterday:
AbbVie axes I-Mab pact to exit fast-thinning race for CD47 space:
https://www.fiercebiotech.com/biotech/abbvie-axes-i-mab-pact-exit-fast-thinning-race-cd47-space
Better alternatives coming in the TP53 treatment area.... here's hoping!
ATVB
Good morning PCS1954, I trust you are well, Great Dunmow is lovely! - We are Brentwood way - it really has it all here, just enough hustle and bustle whilst the ancient woods & green spaces are stunning! (Not to mention Shenfield to Stratford in one stop is a bonus for watching the mighty Hammers!) - That's not to say another move a little further to the Essex/Suffolk borders won't happen once "the boss" agrees!!! - Similar to your emigration - - Family originate from Silvertown, North Woolwich, Plaistow, and we have setup home at various stops on the way out East over the generations.
ATVB
Pfizer still rocking on with high hopes for Brepocitinib, or just a patent app running its due process?
Patent History
Publication number: 20230293544
Type: Application
Filed: Mar 8, 2023
Publication Date: Sep 21, 2023
Applicant: PFIZER INC. (New York, NY)
https://patents.justia.com/patent/20230293544
"Thus, a significant number of patients (˜40%) with moderate to severe HS did not respond to treatment with adalimumab, and therefore there is still an unmet need for an effective, safe, and well tolerated treatment in patients with moderate to severe HS. Disclosed herein is the discovery that compounds and analogues which inhibit certain kinases such as JAK1 and Tyk2 are useful for treating HS. Accordingly, described herein are methods of reducing the severity of HS symptoms in a human subject. These methods can include the step of administering to the subject a pharmaceutical composition comprising such compounds that is effective to reduce the number and/or size of inflammatory lesions (e.g., nodule. abscesses. or draining fistulas), prevent their progression, reduce the pain caused thereby, or delay further lesion development.
SUMMARY OF THE DISCLOSURE
The present disclosure provides a method for treating hidradenitis suppurativa in a subject to achieve a reduction in flare and elevated levels of HiSCR response.
The present method comprises administering to the subject in need thereof certain compounds disclosed herein that inhibit JAKs, such as JAK1 and Tyk2, in a particular dosage and/or in a particular methodology or treatment regime."
ATB
Ahfam, I wholeheartedly agree, SDC1802 as many have said here before, is potentially the biggie: Read-across from the current trials with 1801 is undoubtedly paramount to the very future of Sareum, - in more ways than one ;)
It feels like we really are approaching the endgame.
ATVB
this is rather out there, but i am sharing nonetheless as one or two of our science folks might apreiciate it...... apologies to all the non-nerds, but this is quite fascinating (imo).
robust small molecule-aided cardiac reprogramming systems selective to cardiac fibroblasts:
https://www.biorxiv.org/content/10.1101/2023.09.20.558597v1
direct .pdf: https://www.biorxiv.org/content/10.1101/2023.09.20.558597v1.full.pdf
summary
direct cardiac reprogramming to induce cardiomyocyte-like cells, e.g. by gmt (gata4, mef2c and tbx5), is a promising
route for regenerating damaged heart in vivo and disease modelling in vitro. supplementation with additional factors and
chemical agents can enhance efficiency but raises concerns regarding selectivity to cardiac fibroblasts and complicates
delivery for in situ cardiac reprogramming. here, we screened 2000 chemicals with known biological activities and found
that a combination of 2c (sb431542 and baricitinib) significantly enhances cardiac reprogramming by gmt. without
gata4, mt (mef2c and tbx5) plus 2c could selectively reprogram cardiac fibroblasts with enhanced efficiency, kinetics,
and cardiomyocyte function. moreover, 2c significantly enhanced cardiac reprogramming in human cardiac fibroblasts.
2c synergistically enhances cardiac reprogramming by inhibiting alk5, tyk2 and downregulating oas2, oas3, serpina3n
and tgfbi. 2c enables selective and robust cardiac reprogramming that can greatly facilitate disease modelling in vitro
and advance clinical therapeutic heart regeneration in vivo."
&
"c2 is a pan-jak inhibitor, and consistent with our study, two jak inhibitors (erlotinib and ruxolitinib) can also reportedly enhance cardiac reprogramming, as indicated by elevated expression of cardiomyocyte markers 13. similarly, znf281 has been shown to improve cardiac reprogramming by modulating inflammatory gene expression 57. these reports, in conjunction with our findings in this study, highlight the inhibitory role of jak-stat signalling in cardiac reprogramming. however, only a few pan-jak inhibitors that share a structural similarity with c2 can enhance cardiac fibroblast reprogramming to efficiently induce spontaneous beating icms, indicating that more complicated mechanisms likely underpin c2 enhancement of icms. here, we found that c2 promotes cardiac reprogramming via suppression of c1 activated molecular barriers, such as tgbfi and serpina3n, which may account for their synergistic effects.
in summary, we established a robust cardiac reprogramming system to convert mouse or human cardiac fibroblasts into
cardiomyocytes selectively and efficiently, opening new potential avenues for clinical translation of targeted
reprogramming by optimizing reprogramming ****tails and reducing the number of genetic factors."
as i said, nerdy as can be!
atb, off for a stroll.
Golidocitinib Granted Priority Review by China NMPA for the Treatment of r/r PTCL:
https://finance.yahoo.com/news/golidocitinib-granted-priority-review-china-122600423.html
"Dizal, a spinoff of AstraZeneca's oncology translational science center, has established a portfolio of five clinical-stage assets with global competitiveness. Among these, golidocitinib represents a major research achievement deeply rooted in the principles of translational science. Dizal was the first to identify and validate the JAK/STAT pathway as a highly promising therapeutic approach for PTCL, leading to the development of golidocitinib as the world's first and currently the only JAK1-only inhibitor in pivotal trial for T cell lymphoma."
ATB
Identification of selective inhibitors for Janus kinase 1: an integrated drug repurposing strategy for breast cancer:
https://link.springer.com/article/10.1007/s11696-023-03070-1
"Results from this study have predicted exatecan, fosnetupitant and ubrogepant as viable drugs. Therefore, JAK1 inhibition has been suggested as a possible way to target breast cancer. Additional validation employing in vitro studies may aid in identifying the bioactivity of selected compounds, enabling their application in mitigating this disease condition."
ATB
Apologies - the missing link:
https://www.pharmaceutical-technology.com/news/merck-kgaa-links-with-benevolentai-and-exscientia-to-expand-ai-capabilities/?cf-view
ATB
Merck KGaA links with BenevolentAI and Exscientia to expand AI capabilities:
Exscienta link could be interesting... they have an early stage CHK1i:
"BEN-8744 is a PDE10 inhibitor for the treatment of ulcerative colitis and BEN-28010 is a CHK1 inhibitor for the treatment of glioblastoma multiforme.
Under the collaboration, the Oxford, UK-based Exscientia will receive an upfront cash payment of $20m from Merck with the potential to earn milestone payments of up to $674m in aggregate, if all milestones for all three initial programmes are achieved. The company will recognise the $20m payment on its H2 2023 results as cash inflows. Merck KGaA may also give Exscientia tiered royalties on sales ranging from mid-single-digits to low-double-digits."
Tenuous, additional CHK1i piece:
Derivation of Naïve Human Embryonic Stem Cells Using a CHK1 Inhibitor:
https://link.springer.com/article/10.1007/s12015-023-10613-2
ATB