Macrocyclic Compounds for Tumor Vascular Remodeling
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Solution Overview
Problem
Current anti-cancer drugs lack effective tumor vascular remodeling effects and anti-CAF (Cancer Associated Fibroblast) activity, which are crucial for improving the cancer microenvironment and inhibiting tumor growth.
Innovation Solution
Development of macrocyclic compounds, such as those represented by Formula (I), which exhibit tumor vascular remodeling effects and anti-CAF activity, potentially used in treating various cancers by inhibiting mitosis and tumor growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-cancer drugs are used, then tumor growth inhibition is achieved, but tumor vascular remodeling effects and anti-CAF activity are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of macrocyclic compounds (Formula I) through variations in ring size, substituent groups, and stereochemistry to optimize both tumor vascular remodeling effects and anti-CAF activity. This involves changing molecular parameters such as ring chain length, functional group positions, and spatial configuration to achieve the desired dual therapeutic effect.
2Reliability
If macrocyclic compounds with dual activity are developed, then tumor vascular remodeling and anti-CAF effects are improved, but drug complexity increases
Solution Approach 1:
The patent implements universality by designing macrocyclic compounds that simultaneously perform multiple functions: inhibiting tumor growth, remodeling tumor vasculature, and suppressing CAF activity. The compounds of Formula (I) are structured to interact with multiple biological targets (tubulin, vascular endothelial cells, and fibroblasts) through their macrocyclic core and strategically positioned functional groups, achieving multi-functionality in a single molecular entity.
3Productivity
If tubulin polymerization inhibition is enhanced, then mitosis inhibition is improved, but vascular remodeling effects may be compromised
Solution Approach 1:
The patent applies local quality by differentiating the functional roles of specific regions within the macrocyclic molecule. The macrocyclic core structure (Formula I) provides the primary tubulin-binding activity for mitosis inhibition, while specific substituent groups at defined positions (R1-R6 groups) are optimized to confer vascular remodeling and anti-CAF properties. This spatial differentiation of functional qualities within the single molecule allows simultaneous optimization of multiple therapeutic effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The macrocyclic compounds demonstrate significant antitumor effects by remodeling tumor vasculature and reducing CAF activity, thereby enhancing the cancer microenvironment and inhibiting tumor growth, as shown in preclinical models.
Implementation Method 1
Halichondrin B has demonstrated in vitro inhibition of tubulin polymerization, microtubule assembly, beta 5-tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis
Implementation Method 2
Eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to the elimination of inner tumor hypoxia
Implementation Method 3
Cancer associated fibroblasts (CAFs), which are widely found in a variety of solid tumors, are stromal cells. It is well known that CAFs play an important role in angiogenesis, invasion, and metastasis
Data Source
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AI summary
The present invention provides novel compounds (e.g., compounds of Formulae (I), (II), (III), (IV)) having tumor vascular remodeling effect and/or anti-CAF (Cancer Associated Fibroblasts) activity, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable carrier, and a medical uses thereof.