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I will add that any resistance issues would not pose any problems with regards to our Chk1 in combo for lung cancers.

The real problematic cancers are breast, ovarian and pancreatic. A vast market in dire need of more effective treatments.

Regards

The whole point of the Chk1 cycle checkpoint is to block mutated cells at the P53/TP 53 point . Cell cycle arrest. Some cancers have a resistance already whilst others can and will over time develop resistance. However P53 cell cycle arrest point is only applicable in just over 50% of tumour cancers.
Combination therapy is extremely effective ie Chk1 Pd 1 plus gemcitabine in some cancers. The potential to maintain efficiency may be achieved with P13k or an ATK inhibitor.
The work that Michelle Garrett and crew have carried out is phenomenal and at least equals the work carried out by Sierra oncology. Michelle Garret a strong supporter of the Chk1.

Overall, at the very least this this should make any Chk1 inhibitor far more valuable. Are or were GSK aware of these developments l do not know. I would suggest they were mid 2021.

All looking good. ATK inhibitors already approved for treatment in some cancers.
Not a case of if Chk1 will be used in the clinic, more of a case of when.

Regards

Last post of the night for me.
Costs of treating breast cancers ( USA)

One study looked at costs allowed by insurance companies for breast cancer surgery, chemo, radiation, medications, and certain other medical costs for women ages 18-64. It found costs were higher soon after diagnosis, when surgeries were common. They went down once the approach shifted to chemotherapy.

Specifically:

For women diagnosed with stage 0 breast cancer (small, localized tumors), these medical costs totaled $48,477, on average, 6 months after diagnosis. The total rose to $71,909 after 2 years.
For stages I and II (tumors had not grown deeply into nearby tissues), the range was $61,621-$97,066
For stage III (larger tumors that spread to nearby areas), $84,481-$159,442
For stage IV (affecting other parts of the body), $89,463-$182,655
The American Cancer Society looked at medical costs in a different way. In a case study, after one woman was diagnosed with stage I breast cancer, she had a lumpectomy and biopsy. Later, she had chemotherapy, radiation, daily hormone therapy pills, and regular visits to a primary care doctor and oncologists.

Her total health care costs in her first year of treatment were $144,193. Her expenses for co-pays and coinsurance, deductibles, and premiums would total:

$5,819 with employer-sponsored insurance
$10,114 with a health plan bought in the marketplace
$8,793 with Medicare

Full link to the above
https://www.webmd.com/breast-cancer/breast-cancer-costs#:~:text=Specifically%3A%201%20For%20women%20diagnosed%20with%20stage%200,IV%20%28affecting%20other%20parts%20of%20the%20body%29%2C%20%2489%2C463-%24182%2C655

ovarian cancer cost
On average, the women paid $211,940 each for their treatments, with costs breaking down along the following lines:

$127,365 for hospital charges
$57,597 for pharmacy charges
$26,978 for physician charges

full lnk below
https://justiceguardians.com/ovarian-cancer-treatment-cost/#:~:text=On%20average%2C%20the%20women%20paid%20%24211%2C940%20each%20for,for%20pharmacy%20charges%203%20%2426%2C978%20for%20physician%20charges

Regards

There are over 45 pages of research data in this topic of CHK1 resistance.
We now know that progress has been made with regards to CHK1 inhibition.
Our 737 provided data earlier on but later CHK1 compound CCT244747 supplied by MedKoo Biosciences

The science has not changed at all, it just never stops.

Now if we hear of a success with a CHK1 inhibitor in combo with a P13K or AKT inhibitor we will know where this sucess originated.

It certainly looks very promising for the treatment of breast cancers!

Regards

Taken from the research paper by Michelle Garrett from May 2021.

'The data reveals an NF-kB regulated pathway controlling CHk1 activity in cancer cells and identifies a potential mechanism for both acquiring and overcoming CHK1 inhibitor resistance in cancer patients'

We have as many of us know involvement with CHK1 inhibitor.

Several companies have discontinued development. One reason may be and is very likely to be resistance to CHK1 inhibition.

CHk1 inhibitor extremely effective up until inhibitor resistance is identified. Now some forms of cancer already have this resistance to CHK1 inhibition outright prior to any treatment.

I therefore will repeat
'The data reveals an NF-kB regulated pathway controlling CHk1 activity in cancer cells and identifies a potential mechanism for both acquiring and overcoming CHK1 inhibitor resistance in cancer patients'

A fair size problem and would need to be overcome to be effective in difficult to treat cancers.

This investigational paper compiled by Michelle Garrett and her colleagues have identified this short coming MAY 2021'

Now not only have they identified the short coming ( which is 90% of the problem) but also a method of overcoming resistance to CHK1 inhibition.
Note carefully the excerpt. :-
' The dramatic loss of CHK1 signalling we observed in the C- Rel Eu-Myc lymphoma cells raised the question of how these cells were surviving and coping with ongoing DNA replication stress. Especially given our previous observation that lymphomas in these mice arise earlier than in wild type controls.
The activation of compensatory signalling pathways is a major contributing factor in the development of resistance to kinase inhibitors and often goes hand in hand with the tumour cell having bypassed the need for the drug target, which we observed in our models of both de novo and acquired resistance.'

' Nonetheless, our data suggests that down regulation or mutation of USP 1 is likely to be a common feature in patients undergoing therapy with a CHK 1 inhibitor. Not only will loss of USP1 lead to loss of the target of the inhibitor, but will also result in the upregulation of the AKT or ERK pathway as a compensatory mechanism. We propose that should CHK1 inhibitors become commonly used cancer therapeutics, that this pathway of resistance should be investigated further. Our data implies that a treatment with P13K or AKT pathway inhibitor could be an invaluable strategy either in the treatment of patients whose tumours develop resistance to CHK1 inhibition or potential as a combination therapy to enhance the effectiveness of the initial treatment'

Take from the above what you like. If you do not understand the importance of the above and the development of the science involved then not much I can do about that.
This work which would have taken many months was from may last year. It gives the potential to make CHK1 extremely effective in many cancers that are currently extremely di

PARP inhibitors work more effectively with a PD-1 inhibitor too.
CHK1 PD-1 and LDG would appear to be most effective in lung cancer.
cannot confirm effectiveness of CHK1 PARP and LDG ( not find any data ) Exists theoretically as warrants investigation.

A wide variety of cancer indications for CHK1 and PARP.

[0074] Provided for are methods for reducing cellular proliferation of a cell, the method comprising contacting cancerous tumor cells with a combination of a Chk1 inhibitor (e.g., SRA737) and a PARP inhibitor, where the cancerous tumor cells include: bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular cancer, leukemia, lung cancer, lymphoma, mesothelioma, melanoma, myeloma, ovarian cancer, endometrial cancer, prostate cancer, pancreatic cancer, renal cell cancer, non-small cell lung cancer, small cell lung cancer, brain cancer, sarcoma, neuroblastoma, or squamous cell carcinoma of the head and neck cancerous cells.

To summarise here.
If you have a PARP inhibitor its effectiveness can increase as well as the reduction in amount of PARO ingjibitor required thus reducing the side effects.
Also worthy of note is that CHK1 has been used in combination with other PARP inhibitors with greater effect.
The companies that this would prove advantageous too can no longer obtain SRA 737 from Sierra oncology. I cannot foresee GSK selling to a competitor. The only remaining CHK1 I believe left is :-

Prexasertib (LY2606368) is a small molecule checkpoint kinase inhibitor, mainly active against CHEK1, with minor activity against CHEK2. This causes induction of DNA double-strand breaks resulting in apoptosis. It was developed by Eli Lilly but the company announced in 2019 it was dropping prexasertib from active development,[1] although clinical trials continue. Research continues into the efficacy of prexasertib in treatment of acute myeloid leukemia, myelodysplastic syndrome, rhabdomyosarcoma, and medulloblastoma.[2]

Considerably more efficacy can be gained with PARP CHK1 in combo with LDG.

Regards

[0569] Additional trials are conducted with SRA737 in combination with other therapies, including administering a chemotherapeutic agent, administering an antibody or antibody fragment, administering a radiation treatment, administering an external inducer of replication stress, or administering a combination thereof. Other trials are conducted with SRA737 in combination with other therapies, including administering olaparib, niraparib, rucaparib, talazoparib, cisplatin, a ribonucleotide reductase inhibitor, etoposide, SN-38/CPT-11, mitomycin C, or combinations thereof.

[0570] The results of this study confirm the efficacy of SRA737 combination therapy for the treatment of tumors with known genetic alterations expected to confer sensitivity to Chk1 inhibition (FIG. 17). Proof-of-concept clinical activity has been seen in tumor types such as anogenital (e.g., anal), cervical and rectal. The combination of LDG and SRA737 has been well tolerated. This first-in-human clinical study provides proof-of-concept that sub-therapeutic LDG effectively potentiates SRA737 anti-tumor activity.

[0005] In an embodiment, the SRA737 is administered at least twenty-four (24) hours after the administration of the PARPi. In an embodiment, the SRA737 and the PARPi are administered; and subsequently both SRA737 and the PARPi are administered intermittently for at least twenty-four (24) hours. In an embodiment, the SRA737 and the PARPi are administered on a non-overlapping every other day schedule. In an embodiment, the SRA737 and the PARPi are administered on a non-overlapping every 3 day alternating schedule. In an embodiment, the SRA737 and the PARPi are administered on a non-overlapping every 7 day alternating schedule. In an embodiment, the PARPi is selected from the group consisting of: Olaparib, Rucaparib, Veliparib, Niraparib, Iniparib, Talazoparib, Veliparib, Fluzoparib, BGB-290, CEP-9722, BSI-201, EZ449, PF-01367338, AZD2281, INO-1001, MK-4827, SC10914, and 3-aminobenzamine. In an embodiment, the PARPi is Olaparib. In an embodiment, the PARPi is Niraparib. In an embodiment, the PARPi is Rucaparib. In an embodiment, the PARPi is Talazoparib.

Note the use of Niraparib.

An oncogene is a gene that has the potential to cause cancer.[1] In tumor cells, these genes are often mutated, or expressed at high levels.[2]

Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered and malfunctioning. Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead.[3] Most oncogenes began as proto-oncogenes: normal genes involved in cell growth and proliferation or inhibition of apoptosis. If, through mutation, normal genes promoting cellular growth are up-regulated (gain-of-function mutation), they will predispose the cell to cancer; thus, they are termed "oncogenes". Usually multiple oncogenes, along with mutated apoptotic or tumor suppressor genes will all act in concert to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes

PARP
PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

+PARP is therefore able to repair cell damage. unfortunately it will repair damaged/mutated cells. It will allow therefore cancer to proliferate.
+ I will add here that DNA is double stranded. A double helix. Greater explanation below. If a break in a strand occurs PARP will repair and unfortunately we end up with a mutated cell.

https://en.wikipedia.org/wiki/DNA

+ If we can limit PARP we should therefore be able to reduce production of cancer cell proliferation.

+PARP inhibitor. Basically we are looking at blocking the PARP enzyme.
There are companies that have NDA approval for clinical administration of PARP inhibitor.

+Niraparib is one ( GSK)

In April 2020, the indication for niraparib was expanded to include the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy

Platinum-based antineoplastic drugs (informally called platins) are chemotherapeutic agents used to treat cancer. They are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. In this form of chemotherapy, commonly used drugs include cisplatin, oxaliplatin, and carboplatin.

+ Downside of PARP
The most common side effects in studies were low blood cell counts, namely thrombocytopenia (in 61% of patients, severe in 29%), anemia (in 50%, severe in 25%) and neutropenia (in 30%, severe in 20%). Other, mostly mild to moderate side effects included nausea, fatigue, and constipation. In a study running over 250 days (median), 15% of patients had to permanently discontinue niraparib due to adverse effects.

+Clearly room for improvement!
One option is combo therapy.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569567/

the link is below
https://www.researchgate.net/scientific-contributions/Michelle-D-Garrett-38542729
look at
Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway

Then click on download of full text.

hammy374.
I was not going to ramble on but
from the Michelle Garrett squad early 2021. A very lengthy science report with data. CC245737 and CCT244747 ( first is ours and the second I think is Merk).

There are concerns regarding resistance to CHK1 inhibitors. This does not however make CHK1 obsolete, in fact far from it.
an excerpt from:-
' The data reveals an NF-kB regulated pathway controlling CHk1 activity in cancer cells and identifies a potential mechanism for both acquiring and overcoming CHK1 inhibitor resistance in cancer patients'

I am of the very firm opinion that CHK1 inhibitors are here for a long while yet. As opposed to finding an alternative means to prevent the progression of cancer cell mutation it is becoming clear that rather than taking an alternative route it may be prudent to maintain the inhibition of P53 cell cycle checkpoint by the use of a checkpoint one kinase inhibitor and address the problem of cancer cell resistance to CHK1. Combination therapy is the only real effective treatment that indicates success in these areas.

I am sure GSK were and still are very much aware of such developments.

regards

Slightly off the science topic here.

Sierra take on licensee for 737 in 2016
Great work done up to 2020 when all resources put into momo.
Take a look at the in combo patent. Now granted and filed.
A particular individual noted 140k of Nirapirib associated with SO. Does SO purchase Nirapirib or GSK purchase 737?
SO have peanuts.

Who has funded this whether GSK or SO i dont know.
What we do know is 737 PARP and gemcitabine is many fold more effective than if taken as individually as a monotherapy or if administered 2 out of the 3.

Put yourself in GSK shoes. Firstly you would become aware of the activities. As GSK you would have an interest. If successful, you have considerably achieved increase in value of your Niraparib. Furthermore protected by a new patent.

How do you now obtain SRA 737 whilst also noting that 737 in early 2020 had been taken down from the shop window so as to speak around the same time as patent application?

I would suggest much communication between GSK and SO. There does exist uncertainty if you intend on buying the company. ( SO may not be aware of this intent) No guarantee that Momo will reach commercialisation.

We then have very positive phase 3 data for momo around the same time as to Board of SO purchasing shares around the 14 to 15 dollar mark. Followed shortly after by a target price of 55 dollars a share.

Within a few weeks GSK offered full target market price for takeover.
GSk state their primary reason was momo. Whilst this may be arguably true and very difficult to prove otherwise as they made their bid after the success of the phase 3 data. They could have bought momo outright. Question is why they did not.
I would suggest informal ongoing discussions had been going on for at least 18 months. GSK aware that the combo patent has significant value. ( maybe a reason why some were claiming the takeover price was under valued) S) themselves stated that SRA737 may well prove to have a greater commercial value than momo months earlier.

I posted a while ago and have done so on time frames for deals. Circa from start of informal discussions to then formal discussions and deal being made.

I would suggest many informal discussions made. To the lines of, that once your milestone is met we will make an offer of x amount as there exists a degree of uncertainty,, ie risk at the moment.

Once momo given the go ahead, risk removed, full market target price offered. SO at this tmei very soon obligated to pay Gilead circa 300 million ( from memory ) in milestone payment on commercialisation. They did not have anywhere near that level of available funding. I see also see no significant attempt either to address this issue at the time.

So much has benefitted both sides. What are the chances of such a beneficial outcome without months and months of discussions? There is no need for either side to announce informal communications as not legally required.

Enough from me an

WIP good morning.
Cant add much to your post re 737.
SDC1801 dose escalation is the biggy. More important than Psoriasis in a sense as believe we have this 99% in the bag.

Dose escalation vital for determining maximum safe levels of dosing. Dose limiting.
It is these levels that will dicatate what indications we can expect to be successful in ( subject to a degree of efficacy) . All kinase inhibitors will be restricted in some form or other as the higher the dosing regime the greater the effect of off target adverse reactions. No ifs and buts.

The scope for auto immune is mind boggling.
The scope for 737 is huge also. There are really no new effective treatments for lung cancer. 737 in combo as far as I can see appears the best at the moment although we still effectively at preclinical in combo ie with PARP and PD1. Wee 1 also extremely compatible but found no info on preclinical with this combination.

HGSOC and pancreatic cancers are extremely difficult to treat. Unfortunately much of this is due to late stage diagnosis
and by this time the cancer has become well and truly established. Whilst complete remission unlikely but not impossible with current treatments, it is possible to extend life expectancy by around 1 to 3 years. possibly longer with the best of treatments currently available in clinic.
Bare in mind also that our SDC1802 can be used as a supportive treatment to counteract resistance developed by the cancer to current treatments as in patent description.
Potential is huge in all fronts here.

Recent article covid 19
https://www.express.co.uk/life-style/health/1673554/covid-19-long-term-brain-injury

A very pertinent post there Ajithoth. Long term covid is very much under estimated. 2 year old article at the bottom..
1801 may be fine in down regulation of cytokine storm.

Yes, we have therapy clinics and long term testing but sweet fa as medicine.
Symptoms similar to SLE. At the moment we have SLE as possible indication for SLE. Current articles suggest treatment of long term covid with auto immune treatments. It may well be one of the reasons the large pharmas are heading and pushing towards auto immune ie the psoriasis start and then SLE later down the line. Special interest being TYk2 either alone or combined with Jak.
One thing I can feel pretty sure of is, should there be a suitable treatment found suitable for long covid then that market will dwarf the current market turnover in the pharmaceutical world.

1801 may be fine in down regulation of cytokine storm, but would have to prove itself as a competitive viable treatment for long term covid of which known are similar symptoms to SLE. i am not suggesting we have the be all and end all treatment, but surely it makes our Tyk2 Jak1 look all the more attractive.

From Sept 2020
'Bruce Lee of the City University of New York (CUNY) Public School of Health estimated that if 20% of the U.S. population contracts the virus, the one-year post-hospitalization costs would be at least $50 billion, before factoring in longer-term care for lingering health problems. Without a vaccine, if 80% of the population became infected, that cost would balloon to $204 billion.'
Note 'one year post hospitalisation cost'

Further reading below.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471540/
Regards

https://www.fiercebiotech.com/biotech/gsk-plays-white-knight-paying-66m-rescue-speros-oral-antibiotic-after-fda-rejection?itm_source=parsely-api

Good morning WIP. Correct me if l am wrong but understand as it stood, patent for SRA 737 ran to 2033 by adding in combo, patent it would effectively take patent protection to 2039. Combo of course but, that is where it comes into its own.

Am still of the opinion and that extreme benefits to be gained by the addition of 1802.

Although not yet manufactured as such am thinking of the possibilities of GSK in obtaining 1802 for further in combo work albeit at a preclinical stage.

The only update we had from Sar was of noting the takeover of Sierra by GSK. No mention of patents or updates. Am sure Tim and Co would have been made aware of this.

Regards

Note
[0565] In summary, it has been clearly demonstrated that the triple combination therapy of LDG, SRA737 and the anti-PD-L1 agent of B7-H1 provided strong synergistic effect in inducing dramatic anti-tumor regressive activity and established a significant immune microenvironment in SCLC models in mice.

About Zejula (niraparib)
Zejula is an oral, once-daily PARP inhibitor currently being evaluated in multiple pivotal trials. GSK is building a robust clinical development programme by assessing activity across multiple tumour types and evaluating several potential combinations of Zejula with other therapeutics. The ongoing development programme includes several combination studies.
Also look at
https://uspto.report/company/Sierra-Oncology-Inc/patents
https://uspto.report/patent/app/20220184091

Note the dates carefully.

Great post from WIP earlier. I have looked at many probable combinations of which CHK1 is of value and of the opinion that as soon as a Tyk2 Jak1 which can be used as a supportive therapy in combo with CHK1, PD1, PARP and LDG which our SDC1802 is stated in patent description to primarily overcome drug resistance ,

No point in me trying to explain the science as people think am trying to justify why I am invested.

It is only a matter of time before people and pharmas realise what we have .

Regards and just giving the fingers a very light work out.