BRD9 Degrader Compounds for BAF Complex Modulation

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Solution Overview

Problem

Current treatments for BAF complex-related disorders, such as cancer and infections, lack effective methods to target and reduce the levels and activity of BRD9, a component of the BAF complex, which is upregulated in multiple cancer cell lines and involved in cellular antiviral activities.

Innovation Solution

Development of compounds with a BRD9 binding moiety and a degradation moiety, such as ubiquitin ligase binding moieties, to specifically degrade BRD9, thereby depleting the SS18-SSX fusion protein present in synovial sarcoma tumors and modulating the BAF complex activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments are used for BAF complex-related disorders, then current standard care is maintained, but effective reduction of BRD9 levels and activity is not achieved

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidBRD9 levels and activity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and targets BRD9 specifically from the BAF complex using degrader compounds that selectively reduce BRD9 levels. The compounds are designed to bind to BRD9 and facilitate its degradation, thereby removing this harmful component while leaving other BAF complex members intact. This selective extraction resolves the contradiction by achieving effective BRD9 reduction without compromising overall treatment safety.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the molecular state of BRD9 from stable to degraded by introducing compounds that alter its stability parameters. The degrader compounds modify BRD9's cellular fate, transitioning it from a stable protein to a degraded form through proteasomal pathways. This parameter change enables effective reduction of BRD9 levels and activity, resolving the treatment effectiveness issue.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If BRD9 is depleted to treat cancer, then cancer treatment efficacy is improved, but cellular antiviral activities may be compromised

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidcellular antiviral activities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies partial action by selectively depleting BRD9 while attempting to preserve other BAF complex members and cellular functions. The degrader compounds are designed to target BRD9 specifically, with the intention of achieving sufficient cancer treatment efficacy while minimizing impact on antiviral activities. This partial depletion approach resolves the contradiction by balancing tumor treatment needs with preservation of protective cellular functions.

Inventive Principle:

Principle #16Partial or excessive action

3Quantity of substance

If compounds are designed to bind BRD9 and promote degradation, then BRD9 levels are reduced, but compound complexity increases

Engineering Contradiction:

ImproveBRD9 levelsVSAvoidcompound structure complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent segments the compound structure into distinct functional modules: a BRD9 binding moiety, a linker region, and a degradation moiety. This segmentation allows each component to be optimized independently - the binding moiety for specificity, the linker for flexibility, and the degradation moiety for proteasomal targeting. This modular segmentation reduces overall design complexity while achieving effective BRD9 depletion.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses an intermediary linker region that connects the BRD9 binding moiety to the degradation moiety. This intermediary element facilitates the transfer of function from the binding site to the degradation site, enabling BRD9 stabilization and subsequent proteasomal degradation. The intermediary linker simplifies the overall compound design by providing a flexible connection that doesn't require complex direct coupling mechanisms.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 compounds effectively reduce BRD9 levels and activity, providing a new therapeutic approach for treating BAF-related disorders by targeting the BAF complex and potentially enhancing antiviral responses.

Implementation Method 1

agents that degrade BRD9 (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to BAF, BRD9, and/or SS18-SSX

Methodology Applied

Scientific EffectProteasomal degradation: