TCD Sec61 Inhibitors With Selective Protein Secretion Blocking
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Solution Overview
Problem
Existing protein secretion inhibitors lack selectivity for the Sec61 channel, face challenges in manufacture due to structural complexity, and have limitations in bio-availability and distribution.
Innovation Solution
Development of triazacyclododecansulfonamide (TCD)-based compounds that specifically inhibit protein secretion by binding to and disabling components of the translocon, such as Sec61, with a structure defined by Formula (I) and its derivatives, which can be synthesized using conventional organic chemistry methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known secretion inhibitors are used to block protein transport, then protein secretion is inhibited, but selectivity for the Sec61 channel is lacking
Solution Approach 1:
The TCD-based compounds are designed with specific molecular features (triazacyclododecane core with sulfonamide groups and hydrophobic substituents) that create local binding interactions with the Sec61 channel. The compounds selectively target the Sec61 translocon by forming specific interactions with its hydrophobic groove and pore region, achieving local quality in binding specificity while maintaining reliable inhibition of protein secretion through the Sec61 channel.
2Reliability
If complex structural inhibitors are used to achieve specific binding, then binding specificity improves, but manufacturing becomes challenging
Solution Approach 1:
The TCD-based compounds are designed with a segmented molecular architecture consisting of a triazacyclododecane core structure (providing the binding scaffold) and separate sulfonamide functional groups with hydrophobic substituents (providing specificity). This segmentation allows the core structure to be synthesized using conventional methods while the substituent groups can be varied and optimized for specific binding requirements, simplifying manufacturing while maintaining binding specificity.
3Ease of operation
If small molecule inhibitors are used to improve bio-availability, then distribution improves, but molecular weight limitations are imposed
Solution Approach 1:
The TCD-based compounds are designed with optimized molecular weight parameters (maintaining small molecule status for good bio-availability) while adjusting other molecular parameters such as lipophilicity, hydrogen bonding capacity, and molecular volume to enhance distribution properties. The compounds have molecular weights suitable for oral bio-availability but incorporate hydrophobic substituents and sulfonamide groups that improve membrane permeability and tissue distribution, effectively changing parameters to balance molecular weight limitations with distribution requirements.
Data Source
AI summary
Provided herein are triazacyclododecansulfonamide (“TCD”)-based protein secretion inhibitors, such as inhibitors of Sec61, methods for their preparation, related pharmaceutical compositions, and methods for using the same. For example, provided herein are compounds of Formula (I) and pharmaceutically acceptable salts and compositions including the same. The compounds disclosed herein may be used, for example, in the treatment of diseases including inflammation and/or cancer.