Cereblon Binding Units for Selective PROTAC Cancer Therapy
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Solution Overview
Problem
Current E3 ubiquitin ligase binding units used in PROTAC compounds face challenges in selectivity and chemical/metabolic stability, leading to potential off-target effects and toxicities, particularly in degrading SALL4 and Ikaros, which can result in serious side effects.
Innovation Solution
Development of potent and selective E3 ubiquitin ligase binding units, such as cereblon binding units, with improved stability and selectivity profiles for incorporation into PROTAC compounds, ensuring safer and more effective therapeutic use in cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known E3 ubiquitin ligase binding units are used in PROTAC compounds, then potent binding activity is achieved, but off-target degradation occurs leading to toxicities
Solution Approach 1:
The patent modifies specific local regions of the E3 ligase binding unit (cereblon binder) by substituting particular atoms (e.g., XG, XH, XJ, XK being N, C, S, or O) to create selective binding properties. This local modification approach maintains potent cereblon binding while reducing off-target effects on proteins like SALL4 and Ikaros, thereby resolving the contradiction between binding potency and selectivity.
Solution Approach 2:
The patent systematically varies chemical parameters of the E3 ligase binding unit including substituent types (RA1, RA2), ring structures (Z, ZA, ZB), and heteroatom positions to optimize the balance between binding affinity and selectivity. By changing these molecular parameters, the invention achieves potent cereblon binding while minimizing degradation of unintended targets, thus resolving the reliability versus harmful factors contradiction.
2Productivity
If known E3 ubiquitin ligase binding units are used in PROTAC compounds, then degradation efficacy is achieved, but chemical and metabolic stability is poor
Solution Approach 1:
The patent optimizes chemical stability by modifying molecular parameters including selecting specific heteroatoms (N, O, S) at key positions (XG, XH, XJ, XK), choosing appropriate ring structures (Z, ZA, ZB), and selecting stable substituent groups (RA1, RA2). These parameter changes enhance both chemical stability and metabolic stability while preserving degradation efficacy, with compounds showing less than 20% degradation after 72 hours in human microsomes.
Solution Approach 2:
The patent creates composite molecular structures combining the E3 ligase binding unit with specific linker types and target protein binding units. The linker acts as a composite element connecting the cereblon binder to the target binder, and its structure is optimized to enhance overall compound stability while maintaining degradation function. This composite approach resolves the contradiction between efficacy and stability.
3Productivity
If known E3 ubiquitin ligase binding units are used in PROTAC compounds, then target degradation is achieved, but metabolic stability is poor
Solution Approach 1:
The patent enhances metabolic stability by optimizing molecular parameters including selecting metabolically stable ring structures (aromatic or heteroaromatic Z groups), choosing stable substituent patterns (RA1, RA2), and positioning heteroatoms (N, O, S) at metabolically resistant positions. These changes extend the duration of action in vivo while preserving the degradation function, with compounds demonstrating extended half-lives and sustained target degradation.
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
The new E3 ubiquitin ligase binding units provide enhanced stability and selectivity, reducing off-target effects and improving the safety profile of PROTAC compounds, enabling more effective targeting of intended proteins while minimizing unintended degradation.
Implementation Method 1
the PROTAC binds to both the target protein and E3 ubiquitin ligase simultaneously to form a ternary complex
Implementation Method 2
The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein
Implementation Method 3
the ubiquitinated target proteins are recognized and degraded by the cell's proteasome machinery
Data Source
AI summary
The specification generally relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, where A, Z, Y, RA, Linker and v have any of the meanings defined herein. This specification also relates to the use of such compounds and pharmaceutically acceptable salts thereof in methods of treatment of the human or animal body, for example in the prevention or treatment of cancer. This specification also relates to processes and intermediate compounds involved in the preparation of such compounds and to pharmaceutical compositions containing them.