RE: Competition failing13 Feb 2022 09:20
Abstract from 2011. This is circa 5 years before our CHK1 was licenced to Sierra
Abstract
Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor-induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors.
Now note from the above
'but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents'
This is not the case with SRA737. Clearly all CHK1 inhibitors are not the same. The formulation of the molecules which make up the compounds are not the same. Ours has been shown to work with great toxicity and safety concerns. Further development with PARP inhibitors. LDG and LDG plus immunotherapy checkpoint inhibitors.
I cannot find the Sierra report on SRA 737, low dose Gemcitabine plus ICI's but from memory was outstanding, this being preclinical of course.
It does appear some people becoming a little concerned as to toxicity of our SDC compounds.
Now for a product to be come effective in treating a target it has to be administered at a high enough level. Remember the doses of 30 times treatment dose. Nothing at this stage. Tim then mentioned we may have to try 100 times treatment dosage to reach an MTD. No idea if this was ever achieved.
Treatment levels are from 12.5 mg per day ( whole body ) up to a maximum of 10mg per kilo of bodyweight ( maximum 1000mg total body)
Now compare this with other compounds Baricitinib, More confusingly is, Baricitinib has for some reason been listed in TYK2 development/ in use. It is a JAK1 Jak2 inhibitor. However maximum dose is 4mg and if some signs of concern arise this can be reduced to 2mg per day.
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