Carborane ERβ Agonists for Selective Receptor Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The development of compounds with estrogen receptor (ER) subtype selectivity is challenging due to the structural similarity of ERα and ERβ ligand binding domains, limiting the effectiveness and safety of estrogen-based therapies for conditions like breast cancer, endometrial cancer, thromboembolisms, and strokes.
Innovation Solution
Carborane compounds and carborane analogs are developed as ERβ agonists, offering selective binding to ERβ and potentially treating fibrotic conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), with specific formulations defined by various chemical structures and functional groups.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective estrogen receptor modulators are used, then both ERα and ERβ are activated, but this causes serious adverse effects including increased risk of breast cancer, endometrial cancer, thromboembolisms, and strokes
Solution Approach 1:
The patent applies segmentation by designing compounds that selectively target specific ER subtypes (ERα or ERβ) rather than activating both receptors simultaneously. This is achieved through structural modifications to the ligand molecule that create subtype-specific binding affinity, thereby segmenting the therapeutic effect to activate only the desired receptor pathway while avoiding activation of the other subtype that causes adverse effects
Solution Approach 2:
The patent employs local quality by introducing specific functional groups and structural features at particular positions on the ligand molecule to enhance binding selectivity for a specific ER subtype. These localized structural changes modify the interaction characteristics between the ligand and the ligand-binding domain of the target receptor subtype, creating preferential binding at the molecular level while maintaining overall ligand functionality
2Object-affected harmful factors
If compounds with ER subtype selectivity are developed, then adverse effects are reduced, but the development is challenging due to structural similarity of ERα and ERβ ligand binding domains
Solution Approach 1:
The patent applies asymmetry by designing ligand structures with specific chiral centers and asymmetric functional group arrangements that exploit subtle differences in the three-dimensional configuration of the ERα and ERβ ligand-binding domains. These asymmetric features create stereoselective binding preferences, allowing the ligand to distinguish between the two receptor subtypes despite their overall structural similarity
Solution Approach 2:
The patent employs parameter changes by systematically modifying key structural parameters of the ligand molecule, including bond lengths, bond angles, substituent positions, and functional group types. These parameter adjustments fine-tune the ligand's steric and electronic properties to optimize binding affinity and selectivity for the target ER subtype, transforming a challenging structural problem into a systematic optimization process
Data Source
AI summary
Disclosed are method of treating fibrotic conditions using carboranes and carborane analogs. Also disclosed herein are compounds comprising dicarba-closo-dodecaborane or a dicarba-closo-dodecaborane analog. The compounds can be, for example, estrogen receptor beta (ERβ) agonists. In some examples, the compounds can be selective ERβ agonists. Also provided herein are methods of treating, preventing, or ameliorating cancer in a subject, suppressing tumor growth in a subject, treating an inflammatory disease in a subject, treating a neurodegenerative disease in a subject, treating a psychotropic disorder in a subject, or a combination thereof, by administering to a subject a therapeutically effective amount of one or more of the compounds or compositions described herein, or a pharmaceutically acceptable salt thereof.