Macrocyclic Sonic Hedgehog Modulators for Specific Binding
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Solution Overview
Problem
Current small molecule modulators of the Sonic Hedgehog signaling pathway are limited in effectively targeting and inhibiting the pathway for treating proliferative diseases, pulmonary diseases, and developmental disorders, as they often act downstream of key receptors and lack specificity in binding to the Sonic Hedgehog protein.
Innovation Solution
Development of novel macrocyclic compounds that directly bind to the Sonic Hedgehog protein, inhibiting its induced-protein transcription by preventing the formation of functional complexes with Patched1, thereby targeting the pathway upstream of Ptc1 and interfering with signal relay to Smoothened.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current small molecule modulators are used to inhibit the Sonic Hedgehog signaling pathway, then the pathway can be blocked for treating diseases, but the modulators lack specificity in binding to the Sonic Hedgehog protein and act downstream of key receptors
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure parameters of small molecule modulators, specifically developing macrocyclic compounds with specific ring sizes, functional groups, and stereochemical configurations. These structural parameter changes enable the modulators to bind specifically to the Sonic Hedgehog protein with high affinity, addressing the lack of specificity while maintaining manageable structural complexity through systematic molecular design
Solution Approach 2:
The patent employs composite materials by creating macrocyclic compounds that combine multiple functional moieties within a single molecular framework. These composite structures include specific heteroatoms, functional groups, and spatial arrangements that work synergistically to achieve high-specificity binding to the Sonic Hedgehog protein, resolving the contradiction between specificity and structural complexity
2Reliability
If small molecule modulators act downstream of Patched1, then they can inhibit the pathway, but they cannot interfere with signal relay to Smoothened at the source
Solution Approach 1:
The patent applies the intermediary principle by designing macrocyclic compounds that specifically bind to the Sonic Hedgehog protein, acting as an intermediary that blocks the interaction between Sonic Hedgehog and Patched1. This upstream intervention prevents the formation of the Shh-Ptc1-Smo signaling complex, effectively interfering with signal relay to Smoothened at the source while maintaining pathway inhibition effectiveness
3Reliability
If macrocyclic compounds are designed to bind specifically to Sonic Hedgehog protein, then specificity is improved, but the synthesis complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the synthesis of complex macrocyclic compounds into modular stages, using protected intermediates that can be prepared separately and then assembled. This segmented approach to synthesis allows for the creation of highly specific macrocyclic binders while managing manufacturing complexity through systematic protection-deprotection sequences and modular construction
Data Source
AI summary
The present invention relates to macrocyclic small molecule inhibitors of the Sonic Hedgehog signaling pathway, syntheses thereof, and intermediates thereto. Such small molecule modulators of the Sonic Hedgehog signaling pathway are useful in the treatment of proliferative diseases (e.g., basal cell carcinoma, Gorlin syndrome, medulloblastoma, or pancreatic cancer), pulmonary diseases (e.g., interstitial pnuemonitis or interstitial pulmonary fibrosis), and developmental disorders (e.g., phocomelia or cyclopia). Novel non-natural macrocycles are provided that inhibit Sonic Hedgehog induced-protein transcription.