Cereblon-Binding Compounds with Stable Linkages
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Solution Overview
Problem
Current cereblon modulating agents (CMAs) face challenges in achieving desired substrate specificity for the CRL4CRBN ubiquitin ligase complex, leading to potential safety issues and resistance in cancer therapy, while also being prone to chemical degradation.
Innovation Solution
Development of novel compounds, such as those represented by Formulas (I), (IIa)-(IIc), (III), and (IV), which bind to cereblon and modulate the substrate specificity of the CRL4CRBN complex, potentially offering improved stability and safety profiles by altering substrate recognition and degradation pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing Cereblon Modulating Agents (CMAs) are used to treat cancer, then antitumor activity is achieved, but chemical degradation occurs leading to loss of potency
Solution Approach 1:
The patent modifies the chemical structure of existing CMAs by replacing the hydrolytically labile hydrazide linkage with chemically stable isosteric linkages (amidine, amidine, triazole). This parameter change in chemical bond stability eliminates susceptibility to hydrolytic degradation while maintaining the ability to bind cereblon and modulate substrate specificity, thereby ensuring consistent drug potency over time.
2Object-affected harmful factors
If CMAs are used to achieve desired substrate specificity, then cancer cell proliferation is inhibited, but safety issues and resistance develop
Solution Approach 1:
The patent applies local quality modification by making selective changes to specific regions of the CMA molecule - particularly the linkage region between pharmacophores - while preserving the intact cereblon-binding pharmacophores. This localized modification allows the drug to maintain its ability to induce degradation of specific oncogenic substrates (like IKZF1 and IKZF3) while avoiding degradation of substrates associated with teratogenicity, thereby improving the safety profile without sacrificing substrate specificity.
3Stability of the object's composition
If novel compounds are developed to improve stability, then resistance to hydrolytic degradation is achieved, but complexity of compound structure increases
Solution Approach 1:
The patent extracts and removes the problematic hydrazide linkage component from the CMA structure, which is responsible for hydrolytic degradation. By taking out this unstable element and replacing it with inherently stable isosteric linkages (amidine, amidine, triazole), the invention achieves resistance to hydrolytic degradation without significantly increasing overall molecular complexity. The replacement linkages are structurally similar in size and bonding characteristics, maintaining simplicity while improving stability.
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 enhance the therapeutic efficacy by broadening the range of cancer types responsive to treatment, reducing teratogenicity, and improving drug stability, thus overcoming resistance and safety concerns associated with existing CMAs.
Implementation Method 1
Chemical modulation of cereblon may induce association of novel substrate proteins, followed by their ubiquitination and degradation.
Implementation Method 2
Cereblon is a substrate recognition component of CRL4CRBN. Chemical modulation of cereblon may induce association of novel substrate proteins, followed by their ubiquitination and degradation.
Data Source
AI summary
The present invention discloses novel compounds which bind to cereblon, and methods of use thereof. The compounds are represented by Formulas (I), (IIa)-(IIc), (III) and (IV), below.