Eribulin ADC Conjugates Using C34 Linkers for Higher Stability
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Solution Overview
Problem
Current ADCs using Eribulin as a payload lack stability and specificity, particularly when the linker is introduced at the amino group of C35, and there is a lack of research on using the hydroxyl group at C34 for targeted delivery to tumor cells.
Innovation Solution
Design and synthesis of ADC molecules with Eribulin or its derivatives, incorporating linkers that connect to the hydroxyl group at C34, forming stable ligand-drug conjugates with improved targeting and delivery to tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a linker is introduced at the amino group of C35 in Eribulin, then the ADC can be constructed, but the stability and specificity of the ADC are insufficient
Solution Approach 1:
The patent changes the connection parameter from the amino group at C35 to the hydroxyl group at C34, and further modifies it to a carbonyl group at C34 through oxidation. This parameter change resolves the stability issue while maintaining manufacturability, as the carbonyl group provides better chemical stability for ADC construction.
Solution Approach 2:
The patent applies local quality modification by specifically modifying the hydroxyl group at C34 to a carbonyl group, while keeping the rest of the Eribulin structure intact. This localized modification improves the overall ADC stability without affecting the microtubule inhibition activity of the Eribulin core structure.
2Object-affected harmful factors
If Eribulin is used as a payload in ADC, then anti-tumor activity can be achieved, but the targeting specificity to tumor cells is insufficient
Solution Approach 1:
The patent introduces a linker as an intermediary component between the Eribulin payload and the targeting antibody. The linker connects to the carbonyl group at C34 of Eribulin, forming a stable ADC structure that maintains the microtubule inhibition activity while enabling specific delivery to tumor cells through the antibody component.
3Adaptability or versatility
If the hydroxyl group at C34 is used for linker connection, then new ADC structures can be formed, but the stability is not sufficient
Solution Approach 1:
The patent transforms the hydroxyl group at C34 into a carbonyl group through oxidation, changing the chemical parameter from -OH to C=O. This parameter change significantly improves the stability of the ADC conjugate while still allowing linker attachment, thus resolving the contradiction between versatility and stability.
Data Source
Figure 1A~1C
Figure 1D~1F
Figure 2A~2C
AI summary
A conjugate of the Eribulin drug or a pharmaceutically acceptable salt or solvate thereof, and a preparation method therefor and the use thereof; a linker-drug conjugate or an isomer, mesomer, racemate, or enantiomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a preparation method therefor and the use thereof; a cytotoxin or an isomer, mesomer, racemate, or an enantiomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and a preparation method therefor and the use thereof.