Heteroaromatic Macrocyclic Ether Inhibits ROS1 and ALK Kinases
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Solution Overview
Problem
Current treatments for oncogenic ROS1 and ALK-positive patients, particularly in the central nervous system, are associated with adverse reactions and inadequate activity against resistance mutations, necessitating the development of CNS-penetrant and TRK-sparing inhibitors for ROS1 and ALK kinase domains.
Innovation Solution
The use of a heteroaromatic macrocyclic ether compound, such as Compound 1, or its stereoisomers or pharmaceutically acceptable salts, for treating solid tumors by administering a therapeutically effective amount to patients with advanced or metastatic ROS1-positive non-small cell lung cancer, including those with CNS metastases, to inhibit ROS1 and ALK signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TRK inhibitors are used to treat ROS1-positive or ALK-positive patients, then kinase inhibition activity is achieved, but adverse reactions particularly in the CNS occur including dizziness, ataxia, gait disturbance, paraesthesia, weight gain and cognitive changes
Solution Approach 1:
The patent applies local quality by designing a compound with differential selectivity: it exhibits strong inhibitory activity against ROS1 and ALK kinases (desired local effect) while showing minimal inhibition against TRK kinases (avoiding harmful local effect in CNS). This is achieved through specific structural features of the heteroaromatic macrocyclic ether compound that enable selective binding to ROS1/ALK ATP-binding sites without significantly interacting with TRK kinases, thereby treating the target cancer while sparing CNS-related TRK functions.
Solution Approach 2:
The patent segments the kinase inhibition function by creating a compound that selectively targets specific kinase families (ROS1 and ALK) while excluding others (TRK). This segmentation is achieved through the molecular structure's specific interactions with ROS1/ALK kinase domains, allowing the drug to divide its inhibitory action to affect only the intended targets and leave TRK-mediated CNS functions untouched.
2Reliability
If existing TRK inhibitors are used to treat ROS1-positive or ALK-positive patients, then kinase inhibition activity is achieved, but inadequate activity against resistance mutations occurs including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure parameters of the inhibitor to enhance its binding affinity and selectivity for ROS1 and ALK kinases, including mutant forms. The heteroaromatic macrocyclic ether structure with specific substituents (such as the R1-R6 groups defined in the patent) allows the compound to maintain effective inhibition across multiple resistance mutations by adapting its binding interactions to accommodate structural variations in the kinase domain while preserving TRK sparing.
3Reliability
If existing TRK inhibitors are used to treat ROS1-positive or ALK-positive patients, then kinase inhibition activity is achieved, but TRK inhibition occurs leading to adverse reactions
Solution Approach 1:
The patent applies local quality by designing a compound with differential selectivity: it exhibits strong inhibitory activity against ROS1 and ALK kinases (desired local effect) while showing minimal inhibition against TRK kinases (avoiding harmful local effect in CNS). This is achieved through specific structural features of the heteroaromatic macrocyclic ether compound that enable selective binding to ROS1/ALK ATP-binding sites without significantly interacting with TRK kinases, thereby treating the target cancer while sparing CNS-related TRK functions.
Data Source
AI summary
Provided herein are methods of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for treating, preventing or managing solid tumor.