DRG-BCL2-1 Compound Design for Mutation-Resistant BCL-2 Inhibition

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Solution Overview

Problem

Current BCL-2 inhibitors, such as venetoclax, face resistance issues in treating cancer due to mutations in the target structure and have side effects, necessitating the development of new compounds that can effectively inhibit BCL-2 without resistance.

Innovation Solution

A novel compound, DRG-BCL2-1, is developed as a BCL-2 inhibitor, which can be administered in various forms to treat proliferative diseases like cancer, including specific stereoisomers and pharmaceutically acceptable derivatives, combined with other therapeutic agents for enhanced efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If venetoclax is used as a BCL-2 inhibitor, then high affinity for BCL-2 is achieved, but resistance develops due to mutations in the target structure

Engineering Contradiction:

Improveefficacy of BCL-2 inhibitionVSAvoidresistance to mutations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs structure-activity relationship (SAR) analysis to systematically modify chemical parameters of the inhibitor molecule. By changing substituent groups at specific positions (R1, R2, R3, R4, R5, R6) and adjusting molecular properties, the invention optimizes binding affinity while maintaining resistance to target mutations, directly addressing the contradiction between efficacy and adaptability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent develops composite chemical structures combining multiple functional groups and scaffolds. The compound of formula (I) integrates various pharmacophoric elements that work synergistically to achieve both high BCL-2 binding affinity and resistance to mutations, effectively resolving the contradiction through molecular composite design

Inventive Principle:

Principle #40Composite materials

2Productivity

If current BCL-2 inhibitors are used, then cancer cell proliferation is inhibited, but side effects occur

Engineering Contradiction:

Improveinhibition of cancer cell proliferationVSAvoidside effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality optimization by introducing specific substituent groups at targeted positions on the molecular scaffold. These localized chemical modifications enhance selective binding to BCL-2 while reducing off-target effects, thereby improving the therapeutic index by addressing proliferation inhibition efficacy while minimizing side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates optimized copies of the BCL-2 binding interface by designing compounds that replicate key interaction features while avoiding problematic regions. The compound of formula (I) copies essential binding pharmacophores but with modified chemical properties that reduce side effects while maintaining anti-proliferative efficacy

Inventive Principle:

Principle #26Copying

Data Source

PatentUS12384746B2Physics-driven discovery of novel small therapeutic compounds for use as a BCL-2 inhibitor

Publication Date: 2025.08.12 BAHCESEHIR UNIVERSITY

AI summary

The invention relates to compound shown with formula (I) or a pharmaceutically acceptable derivative thereof for use as a novel inhibitor of BCL-2.