2-Hydroxybenzoic Acid Derivatives for Selective SIRT5 Targeting
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Solution Overview
Problem
Current therapies lack effective inhibitors or degraders for SIRT5, a sirtuin protein implicated in various cancers and other diseases, necessitating new compounds to target SIRT5 activity for therapeutic intervention.
Innovation Solution
Development of novel 2-hydroxybenzoic acid derivatives and proteolysis-targeting chimeras (PROTACs) that function as SIRT5 inhibitors and degraders, selectively targeting and degrading SIRT5 to treat disorders associated with sirtuin activity, particularly in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used, then treatment of sirtuin-associated disorders is maintained with existing drugs, but effective SIRT5 inhibition or degradation is not achieved
Solution Approach 1:
The invention segments the therapeutic approach by developing distinct compounds for different sirtuin targets (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) rather than using broad-spectrum inhibitors. This allows selective inhibition or degradation of specific sirtuin isoforms, enabling precise targeting of SIRT5-associated disorders while maintaining compatibility with existing therapies for other sirtuin-related conditions.
Solution Approach 2:
The invention introduces PROTAC molecules as intermediary compounds that facilitate SIRT5 degradation through a two-component mechanism: one component binds to SIRT5 while the other recruits an E3 ubiquitin ligase. This intermediary approach enables selective SIRT5 degradation without directly inhibiting its active site, overcoming the limitation of existing therapies that lack effective SIRT5-specific agents.
2Reliability
If new SIRT5 inhibitors and degraders are developed, then effective therapeutic intervention for SIRT5-associated disorders is achieved, but drug development complexity and time increase
Solution Approach 1:
The invention creates a universal platform for sirtuin targeting where modified versions of existing sirtuin inhibitor compounds can function across multiple sirtuin isoforms. The core chemical structures are adapted with specific modifications to achieve selective SIRT5 inhibition or degradation, reducing the need to develop entirely new molecular scaffolds from scratch and streamlining the drug development process.
Solution Approach 2:
The PROTAC molecules represent composite structures combining two functional components: a SIRT5-binding ligand and an E3 ubiquitin ligase recruiter, connected by a linker. This composite approach leverages the properties of both components to achieve SIRT5 degradation, distributing the complexity across modular elements that can be independently optimized and screened.
3Reliability
If selective SIRT5 degradation is achieved, then specific therapeutic benefits for cancer and other disorders are obtained, but off-target effects on other sirtuins may occur
Solution Approach 1:
The invention applies local quality by introducing specific chemical modifications at particular positions on the core inhibitor structures. These localized modifications (such as substituent groups at specific ring positions) confer selective affinity for SIRT5 over other sirtuin isoforms, enabling the compound to distinguish between similar protein targets and reduce off-target effects while maintaining potent SIRT5 inhibition or degradation.
Data Source
AI summary
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a 2-hydroxybenzoic acid structure which function as sirtuin (e.g., SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) inhibitors and/or degraders which function as effective therapeutic agents for treating, ameliorating, and preventing disorders associated with sirtuin activity (e.g., melanoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, non-small cell lung cancer). In addition, this invention also relates to a new class of proteolysis-targeting chimeras (PROTACs) (as defined herein) which function as sirtuin inhibitors and/or degraders within cancer and/or immune cells. Pharmaceutical compositions comprising said compounds are also within the scope of the present invention.