5-Morpholin-4-yl-pyrazolo[4,3-b]pyridine ATR Inhibitors
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Solution Overview
Problem
There is a lack of potent inhibitors for the Ataxia telangiectasia mutated and Rad3-related kinase (ATR) which are essential for treating cancer, as current treatments often activate cell cycle checkpoints in cancer cells, allowing them to survive and resist chemotherapy.
Innovation Solution
Development of 5-Morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives that selectively inhibit ATR, potentially sensitizing cancer cells to replication inhibitors and reducing toxicity to normal cells by targeting the ATR-CHK1 pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer treatments (chemotherapeutic agents and ionizing radiation) are used to induce DNA damage and replication fork stalling, then cell cycle checkpoint pathways are activated, but cancer cells survive and resist chemotherapy due to robust ATR-CHK1 checkpoint response
Solution Approach 1:
The patent introduces ATR inhibitors as intermediary compounds that specifically target and block the ATR kinase enzyme in the DNA damage response pathway. These compounds act as mediators between DNA damage induction and cell death, preventing the activation of protective checkpoint responses while preserving the initial DNA damage effect, thereby converting the harmful checkpoint-mediated survival into therapeutic vulnerability
Solution Approach 2:
The patent employs parameter changes by modifying the biochemical activity level of ATR kinase through inhibition. By reducing ATR enzymatic activity below a critical threshold, the pathway's ability to respond to DNA damage is altered, preventing checkpoint activation and cell cycle arrest that would otherwise protect cancer cells from chemotherapy-induced stress
2Reliability
If ATR inhibition is used to sensitize cancer cells to replication inhibitors, then cancer cell death is enhanced, but toxicity to normal cells may increase
Solution Approach 1:
The patent applies local quality by targeting ATR inhibition specifically in cancer cells that exhibit high replication stress and defective checkpoint control, while normal cells with robust checkpoints can tolerate transient ATR inhibition. The morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives achieve selective toxicity by exploiting the local difference in checkpoint robustness between transformed and untransformed cells
Solution Approach 2:
The patent converts the harmful characteristic of high replication stress in cancer cells into a therapeutic benefit. Cancer cells with oncogene activation or tumour suppressor loss already experience high endogenous replication stress; ATR inhibition exacerbates this stress to lethal levels, transforming the cells' inherent vulnerability into selective susceptibility to the therapy while normal cells remain protected by their lower baseline stress levels
3Reliability
If there were potent ATR inhibitors available, then selective inhibition of ATR-CHK1 pathway could be achieved, but currently there is a lack of such inhibitors for clinical use
Solution Approach 1:
The patent achieves selective ATR inhibition through parameter changes in the chemical structure of the inhibitors. The morpholin-4-yl-pyrazolo[4,3-b]pyridine core structure with specific substituents (R1, R2, R3, R4, R5, R6) creates a molecular configuration that selectively binds to ATR kinase with high affinity and specificity, distinguishing it from other kinases in the PIKK family and enabling selective pathway inhibition
Solution Approach 2:
The patent employs composite molecular design by combining the pyrazolo[4,3-b]pyridine core structure with morpholin-4-yl substitution and various aromatic or heterocyclic groups. This composite structural approach creates a molecule with optimized pharmacokinetic properties, selective target binding, and appropriate solubility characteristics for clinical development
Data Source
AI summary
Compounds of the formula Ia and Ib in which R1, R2 and R3 have the meanings indicated in Claim 1, are inhibitors of ATR, and can be employed for the treatment of diseases such as cancer.