Macrocyclic Compounds Modulating CEP250 via Presenter Protein Binding
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Solution Overview
Problem
Current treatments for diseases related to CEP250, such as cancer and ciliopathies, lack effective compounds that can modulate the activity of CEP250 and associated signaling pathways like Hedgehog, Wnt, and PDGFRalpha.
Innovation Solution
Development of macrocyclic compounds that interact with presenter proteins like FKBP12 and FKBP52 to form complexes with CEP250, enhancing their binding affinity and modulating its activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional small molecule compounds are used to target CEP250, then the compound structure is simple and easy to manufacture, but the binding affinity and specificity to CEP250 is insufficient
Solution Approach 1:
The patent combines a presenter protein (FKBP12 or FKBP52) with a CEP250-binding compound to form a complex. The presenter protein moiety contributes hydrophobic residues and structural features that dramatically enhance binding affinity to CEP250, while the compound moiety provides the basic binding framework. This merging allows the complex to achieve high specificity and affinity (measured by enhanced binding to CEP250 in cellular assays) that neither component achieves alone.
Solution Approach 2:
The invention creates a composite molecular system consisting of a presenter protein fused or complexed with a small molecule compound. The presenter protein portion provides a stable structural core with specific binding interfaces, while the compound portion provides targeted interaction capabilities. This composite structure achieves both the reliability of strong binding and the manufacturability of small molecule-based approaches.
2Reliability
If compounds with high binding affinity to CEP250 are developed, then the treatment efficacy for cancer and ciliopathies is improved, but the complexity of compound design and synthesis increases
Solution Approach 1:
The patent uses the presenter protein as an intermediary that mediates the interaction between the compound and CEP250. The presenter protein serves as a bridge, providing a platform that enhances the compound's ability to bind CEP250 with high affinity. This intermediary approach allows researchers to start with simpler compound structures and achieve high treatment efficacy through the presenter protein's contribution to binding, rather than requiring complex compound designs from the outset.
Solution Approach 2:
The invention segments the binding function into two distinct components: the presenter protein portion that provides structural stability and binding interface, and the compound portion that provides target-specific interaction. This segmentation allows each component to be optimized independently - the presenter protein can be selected from known families (FKBP12, FKBP52) with characterized properties, while the compound can be designed or screened for specific CEP250 interaction, simplifying the overall design and synthesis process.
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
These compounds specifically bind to CEP250 with increased affinity, potentially treating cancers and ciliopathies by modulating its activity and associated signaling pathways.
Implementation Method 1
The compound and a presenter protein form a complex that specifically binds to the target protein
Implementation Method 2
the portion of the molecule that comprises each ring atom that participates in binding to the target protein has a cLogP greater than 2
Data Source
AI summary
The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein such as CEP250. These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of the target protein. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of target protein activity.