Indazole Hydrazide Integrin αvβ3 Antagonist for Resistant Prostate Cancer
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Solution Overview
Problem
Current treatments for castration-resistant prostate cancer (CRPC) face challenges due to drug resistance, particularly against first-generation anti-androgen drugs like abiraterone and enzalutamide, and there is a need for therapies targeting the interaction between tumor cells and the extracellular matrix to combat drug resistance and tumor angiogenesis.
Innovation Solution
Development of an indazole hydrazide compound that acts as an integrin αvβ3 receptor antagonist with anti-tumor angiogenesis activity, inhibiting the interaction between tumor cells and the extracellular matrix, and demonstrating synergistic effects with enzalutamide in enzalutamide-resistant cell lines.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If new anti-androgen drugs such as abiraterone and enzalutamide are used to treat CRPC patients, then survival of patients is prolonged, but primary or acquired drug resistance emerges
Solution Approach 1:
The patent combines two distinct therapeutic mechanisms into a single compound: integrin αvβ3 receptor antagonism and anti-androgen activity. This segmentation of functions allows the compound to simultaneously address multiple pathways involved in CRPC progression and drug resistance, thereby extending patient survival while mitigating resistance development.
Solution Approach 2:
The indazole hydrazide compound represents a composite therapeutic agent that integrates multiple pharmacological activities. By combining integrin receptor blocking capability with androgen receptor antagonism in one molecule, the patent creates a composite drug that targets both tumor-stroma interaction and androgen-driven proliferation, addressing the complexity of CRPC pathogenesis.
2Reliability
If cilengitide is used as an integrin receptor inhibitor against αvβ3, then the interaction between extracellular matrix and integrin receptor is blocked, but anti-tumor activity is relatively weak
Solution Approach 1:
The patent merges the integrin antagonism function with anti-androgen activity into a single molecular entity. This combination allows the compound to simultaneously block the extracellular matrix-integrin interaction and inhibit androgen receptor-mediated signaling, thereby achieving both reliable integrin blockade and enhanced anti-tumor efficacy that cilengitide alone cannot provide.
Solution Approach 2:
The indazole hydrazide compound exhibits multi-functionality by acting as both an integrin αvβ3 receptor antagonist and an anti-androgen agent. This universal activity across multiple therapeutic targets enables the compound to address both the stromal interactions and hormonal drive in CRPC, overcoming the limitation of single-function drugs like cilengitide.
3Productivity
If anti-angiogenesis drugs are used to inhibit VEGF family and its receptors, then tumor angiogenesis is inhibited, but drug resistance develops with long-term administration
Solution Approach 1:
The compound preemptively blocks integrin αvβ3 receptors, which are critical for angiogenesis and tumor-stroma interactions, before resistance can develop. By establishing early blockade of this key pathway involved in both angiogenesis and drug resistance mechanisms, the compound prevents the adaptive responses that typically lead to resistance in long-term anti-angiogenic therapy.
Data Source
AI summary
An indazole hydrazide compound, as represented in formula (I); wherein, R is selected from substituted alkyl, substituted alkenyl and substituted phenyl; substituent in the substituted alkyl and substituted alkenyl includes phenyl and/or substituted phenyl; R′ is selected from H and alkyl. Compared with the prior art, the above indole hydrazide compound can be used as integrin avβ3 receptor antagonist. Besides, it has obvious anti-prostate cancer activity and has a significant inhibitory effect on enzalutamide-resistant cell lines. In addition, the above-mentioned compound has obvious anti-tumor angiogenesis activity and can be used in the preparation of anti-tumor angiogenesis drugs to inhibit tumor angiogenesis.