Estrogen Receptor Modulators Degrade ER to Overcome Resistance
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Solution Overview
Problem
Current treatments for estrogen-related diseases, such as breast cancer and other estrogen-sensitive conditions, face challenges with resistance to anti-hormonal therapies and the need for new agents that can effectively target estrogen receptors, particularly in metastatic disease and resistant tumors.
Innovation Solution
Development of compounds that act as estrogen receptor modulators and degraders, specifically designed to diminish estrogen receptor activity, offering therapeutic benefits by reducing ER levels and inhibiting tumor growth with minimal agonist activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-hormonal therapies are used to treat estrogen-related diseases, then initial therapeutic effect is achieved, but resistance to treatment develops over time
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of estrogen receptor-targeting compounds. The compounds of Formula (I) feature specific structural parameters (aromatic ring systems, substituent positions, stereochemistry) that enable them to induce degradation of the estrogen receptor protein rather than merely blocking it, fundamentally changing the mechanism of action and overcoming treatment resistance
Solution Approach 2:
The invention extracts and targets the estrogen receptor protein itself for degradation, rather than only blocking its function. The compounds specifically bind to and recruit degradation machinery to the estrogen receptor, extracting it from the functional system and eliminating the source of resistance that develops with conventional therapies
2Reliability
If estrogen receptor antagonists are used to block estrogen activity, then tumor growth is inhibited, but agonist activity may still occur causing unwanted effects
Solution Approach 1:
The patent converts the potential harm of agonist activity into a benefit by designing compounds that exclusively induce receptor degradation without any agonist activity. The molecular structure of compounds of Formula (I) is configured to engage the estrogen receptor in a manner that triggers ubiquitination and proteasomal degradation, transforming the therapeutic approach from partial blockade to complete elimination of the target protein
Solution Approach 2:
The invention changes the functional parameter of receptor interaction from partial blockade (antagonism) to complete elimination (degradation). The specific chemical parameters of compounds of Formula (I), including the core aromatic structure and substituent patterns, are optimized to induce conformational changes in the estrogen receptor that signal for degradation rather than simple functional inhibition
3Reliability
If new compounds are developed to overcome resistance, then therapeutic activity is improved, but complexity of drug development increases
Solution Approach 1:
The patent achieves universality by creating a compound series of Formula (I) with a core structural framework that can be systematically modified with different substituents to target various estrogen receptor-positive cancers. The fundamental degradation mechanism remains consistent across different compounds and cancer types, providing a universal therapeutic platform that reduces overall development complexity despite addressing multiple indications
Data Source
AI summary
A compound that has the structure of Formula (XII): wherein, X1 is CH, CR3 or N; X2 is N, CH, or CR3; Z is -OH or -OR10; R2 is C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C3-C6cycloalkyl, or -C1-C4alkylene-W; W is hydroxy, halogen, CN, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, and C3-C6cycloalkyl; each R3 is independently halogen, C1-C4alkyl, or C1-C4fluoroalkyl; each R4 is independently halogen, -CN, -OR9, -S(=O)2R10, C1-C4alkyl, C1-C4fluoroalkyl, or C1-C4heteroalkyl; each R5 is independently halogen, -CN, -OR9, -S(=O)2R10, C1-C4alkyl, C1-C4fluoroalkyl, or C1-C4heteroalkyl; R6 is H, C1-C4alkyl, or halogen; R7 is H, C1-C4alkyl, or halogen; R9 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C6cycloalkyl; R10 is C1-C6alkyl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; or a pharmaceutically acceptable or N-oxide thereof.