RET Inhibitor Compounds Selective Binding Resistant Mutants
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Solution Overview
Problem
Current RET inhibitors are limited in their ability to effectively target both wild-type RET and its resistant mutants, leading to treatment challenges due to toxicities and the development of resistance in cancer therapy, particularly in cancers like papillary thyroid carcinoma and non-small cell lung cancer.
Innovation Solution
Development of specific compounds with structural formulas (A) and their pharmaceutically acceptable salts that inhibit RET and its resistant mutants, allowing for effective treatment of conditions mediated by aberrant RET activity, including cancer, by administering a therapeutically effective amount of these compounds to patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If approved multi-kinase inhibitors are used to treat RET fusion-positive cancers, then RET inhibition activity is achieved, but toxicities occur due to inhibition of other kinase targets
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (Formula I with particular substituent patterns on rings A and B, and specific X1, X2, Y1, Y2 configurations) that confer selective binding to RET kinase over other kinases. This selectivity is achieved through tailored molecular interactions at the RET binding site while avoiding off-target kinase binding, thereby maintaining RET inhibition efficacy while reducing toxicities.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters including substituent types (R1-R9), ring structures (A and B), and linker configurations to optimize the compound's kinetic selectivity for RET. By adjusting these molecular parameters, the compounds achieve enhanced binding affinity and selectivity for RET compared to other kinases, resolving the contradiction between efficacy and toxicity.
2Reliability
If current RET inhibitors are used to treat cancer, then initial treatment response is achieved, but resistance develops limiting further treatment options
Solution Approach 1:
The patent applies universality by developing compounds of Formula I that possess multi-kinase inhibitory activity with a specific focus on RET, but also retain activity against RET mutants. The compounds are designed to target conserved regions of the RET kinase domain that are present in both wild-type and mutant forms, enabling a single compound to effectively treat cancers regardless of RET mutation status, thus extending treatment duration and delaying resistance.
Solution Approach 2:
The patent employs preliminary action by designing compounds with structural features that anticipate and prevent resistance development. The compounds are engineered to bind to RET in a manner that disrupts the conformational changes associated with resistance mutations, effectively preventing the tumor cells from developing resistance mechanisms before they can emerge, thereby extending the duration of effective treatment.
3Reliability
If higher doses of multi-kinase inhibitors are administered to overcome resistance, then RET inhibition is enhanced, but toxicities increase
Solution Approach 1:
The patent applies parameter changes by optimizing the molecular structure of compounds (Formula I) to achieve higher binding affinity and selectivity for RET. By adjusting parameters such as substituent electron-withdrawing groups (R2, R6), ring fusion patterns, and linker lengths, the compounds achieve potent RET inhibition at lower concentrations, eliminating the need for high dosing and thereby avoiding dose-dependent toxicities.
Solution Approach 2:
The patent uses local quality by designing compounds with specific local structural features (such as the heteroaryl or heterocyclyl ring B with particular nitrogen configurations and substituent positions) that create highly selective interactions with the RET kinase binding pocket. This localized optimization of binding interactions enhances RET inhibition potency, allowing effective treatment at lower doses with reduced off-target effects and toxicities.
Data Source
AI summary
Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.