Small Molecule ATF6 Activators for ER Proteostasis
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Solution Overview
Problem
Current therapies lack specific small molecules that effectively activate the ATF6 arm of the unfolded protein response (UPR) to address protein misfolding diseases by preferentially remodeling the endoplasmic reticulum (ER) proteostasis network without inducing global UPR activation or compromising overall proteostasis.
Innovation Solution
Development of a first-generation library of small molecule ER proteostasis regulators identified through high-throughput screening that selectively activate the ATF6 arm of the UPR, demonstrated by cell-based assays and transcriptional profiling, to reduce the secretion and aggregation of destabilized amyloidogenic proteins without affecting stable proteins or the global secreted proteome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If small molecules are used to activate the ATF6 arm of the UPR, then the ER proteostasis network is preferentially remodeled to reduce secretion and aggregation of destabilized amyloidogenic proteins, but there is a risk of inducing global UPR activation or compromising overall proteostasis
Solution Approach 1:
The patent applies local quality by designing small molecules that selectively activate only the ATF6 arm of the UPR pathway while leaving other arms (IRE1 and PERK) unaffected. This selective activation allows preferential remodeling of the ER proteostasis network to reduce secretion of destabilized amyloidogenic proteins without inducing global UPR activation or compromising overall cellular proteostasis
Solution Approach 2:
The patent employs parameter changes by developing small molecules with specific chemical structures and properties that enable selective binding and activation of ATF6. Through high-throughput screening and structure-activity relationship analysis, compounds were optimized to achieve the desired selectivity parameter for ATF6 activation while maintaining appropriate thresholds for avoiding global UPR activation
2Adaptability or versatility
If current therapies are used to address protein misfolding diseases, then treatment is provided, but there is a lack of specific small molecules that effectively activate the ATF6 arm of the UPR
Solution Approach 1:
The patent applies self-service by utilizing high-throughput screening platforms and automated assays to identify and characterize small molecule candidates. The screening process leverages cell-based reporter assays and transcriptional profiling technologies that automatically evaluate compound activity, reducing manual intervention and accelerating the discovery of ATF6-selective activators for therapeutic development
Data Source
AI summary
The invention provides compounds for activating the activating transcription factor 6 (ATF6) arm of the unfolded protein response (UPR), or activating the transcriptional targets of ATF6, in the endoplasmic reticulum of a cell, the compounds being of any of formulas (I) through (IX) as described herein. The compounds can be used for treatment of conditions involving gain-of-toxic-function and loss-of-function folding disorders including lysosomal storage diseases, antitrypsin-associated emphysema and similar diseases. These molecules are also expected to have disease-ameliorating effects in Alzheimer's disease and diabetes.