Trifluoromethylsulfonyl BCL-XL Degrader for Solid Tumor Resistance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing BCL-2 protein inhibitors, such as those targeting BCL-2, have limited efficacy in treating solid tumors, and BCL-XL inhibitors are needed to address tumor drug resistance and progression.
Innovation Solution
Development of a trifluoromethanesulfonyl-containing compound that binds to BCL-XL protein and is used in a PROTAC molecule to induce its degradation through the ubiquitin-proteasome system, utilizing a bifunctional compound capable of binding to a target protein and E3 ubiquitin ligase.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If BCL-2 protein inhibitors are used to treat tumors, then anti-apoptotic activity is improved, but efficacy in solid tumors is limited
Solution Approach 1:
The invention segments the anti-apoptotic target into two distinct protein families: BCL-2 and BCL-XL. By developing separate inhibitors for each target (compound of formula I for BCL-XL, compound of formula II for BCL-2), the patent achieves comprehensive coverage of both pro-survival pathways, thereby overcoming the limitation of BCL-2 inhibitors alone in treating solid tumors while maintaining reliable anti-apoptotic activity
Solution Approach 2:
The patent creates a universal anti-tumor strategy by designing inhibitors that can target multiple BCL-2 family proteins. The compound of formula I targets BCL-XL while the compound of formula II targets BCL-2, together providing broad-spectrum anti-apoptotic coverage that adapts to different tumor types including both leukemia and solid tumors, thus achieving versatility across different cancer indications
2Reliability
If BCL-XL inhibitors are developed to address drug resistance, then tumor progression control is improved, but compound complexity increases
Solution Approach 1:
The patent systematically varies key structural parameters of the BCL-XL inhibitor (compound of formula I) to optimize its properties. By modifying the R substituent (selected from H, F, Cl, Br, CF3, OH, NH2, CN, and C1-6 alkyl groups), the X heteroatom (CH2, NH, or O), and the L connecting group, the invention achieves effective BCL-XL inhibition and tumor progression control while managing compound complexity through structured molecular design
Solution Approach 2:
The compound of formula I represents a composite molecular structure combining multiple functional elements: a core scaffold with variable R substituents, heteroatom bridges (X), and connecting groups (L) that link to additional functional moieties. This composite design enables effective BCL-XL targeting and tumor progression control while organizing complexity into manageable structural components
Data Source
AI summary
The present disclosure relates to the field of pharmaceutical chemistry, relates to a compound containing trifluoromethylsulfonyl, and specifically relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in treating tumor diseases.