ERK Modulating Compounds for Cancer Treatment
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Solution Overview
Problem
Current treatments for cancers with dysregulated MAPK pathways, particularly those with BRAF and RAS mutations, often result in poor prognosis and resistance to therapies, with a need for more effective and tolerable therapeutic options that can modulate ERK activity to inhibit tumor growth and metastasis.
Innovation Solution
Development of small molecular protein-protein interaction disruptors that block negative regulation of ERK, specifically compounds of formula (I) and their pharmaceutical compositions, which can be administered to modulate ERK activity and treat cancers such as melanoma, lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for cancers with dysregulated MAPK pathways, then treatment is provided, but prognosis remains poor and resistance to therapy occurs frequently
Solution Approach 1:
Instead of directly inhibiting ERK activity as conventional approaches attempt, this patent applies the inversion principle by blocking the negative regulation of ERK. The compounds prevent DUSP6-mediated dephosphorylation of ERK, thereby maintaining or enhancing ERK activity. This counterintuitive approach exploits the fact that hyperactivation of ERK leads to cell cycle arrest and cell death in cancer cells, providing a novel therapeutic strategy that overcomes resistance to conventional MAPK pathway inhibitors
Solution Approach 2:
The patent changes the therapeutic parameter from ERK inhibition to ERK activation maintenance. By designing compounds that block DUSP6 function rather than directly targeting ERK or upstream kinases, the invention alters the mechanism of action and achieves durable anti-tumor responses in cancers with BRAF and RAS mutations that have developed resistance to standard therapies
2Object-affected harmful factors
If MAPK pathway inhibition is used, then tumor growth is suppressed, but cell stress increases and cell death occurs due to hyperactivation
Solution Approach 1:
The patent converts the harmful effect of ERK hyperactivation (which causes cell stress and death) into a therapeutic benefit. By blocking DUSP6-mediated negative regulation, the compounds intentionally induce ERK hyperactivation in cancer cells, leading to cell cycle arrest and cell death. The mechanism transforms what would normally be a detrimental pathway activation into a therapeutic mechanism that selectively kills cancer cells while sparing normal cells
Data Source
AI summary
The invention relates to compounds which modulate the activity of ERK. The present invention also relates to processes for the preparation of said compounds, pharmaceutical compositions comprising said compounds, and use of said compounds in the treatment of conditions, diseases and disorders mediated by ERK.