Pyridazinone MYC Modulators via MAX-MYC Interface Targeting
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Solution Overview
Problem
Current small molecule compounds struggle to effectively target and modulate the MYC protein due to its lack of binding sites, making it 'undruggable', and existing therapies for MYC-driven cancers are inadequate.
Innovation Solution
Development of pyridazinone-derived compounds that modulate MYC expression and activity, offering pharmaceutical compositions and methods to reduce or inhibit MYC in cells, including conjugates and complexes, for treating MYC-driven cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule compounds are used to target MYC protein, then therapeutic effectiveness is improved, but binding site availability is insufficient
Solution Approach 1:
The patent employs MAX as an intermediary protein that binds to MYC. The small molecule compounds target the MAX-MYC protein-protein interaction interface rather than binding directly to MYC. This intermediary approach allows the drugs to modulate MYC activity indirectly through disrupting the MAX-MYC complex formation, resolving the contradiction between lacking direct binding sites and achieving therapeutic effectiveness.
2Reliability
If existing therapies for MYC-driven cancers are used, then treatment is provided, but efficacy is inadequate
Solution Approach 1:
The patent modifies the chemical structure of existing MAX interactors by introducing specific pyridazinone moieties and varying substituent groups (R1-R6, Z, d, h, i, j, k, m parameters). These structural parameter changes enhance the compounds' ability to disrupt MAX-MYC interaction, thereby improving treatment efficacy compared to existing therapies while maintaining the same target engagement mechanism.
3Reliability
If pyridazinone-derived compounds are developed, then MYC modulation is achieved, but compound complexity increases
Solution Approach 1:
The patent divides the compound structure into distinct functional segments: a core pyridazinone moiety (providing MAX interaction capability) and variable substituent groups (R1-R6, Z, d, h, i, j, k, m parameters that can be independently optimized). This segmentation allows systematic exploration of structure-activity relationships while maintaining manageable synthetic complexity through modular assembly of standardized building blocks.
Data Source
AI summary
Compositions, systems, and methods are described herein for the modulation, and in particular the reduction or inhibition, of expression or activity of MYC in a cell, animal or human subject. Such compositions, systems, and methods are useful to prevent, ameliorate, or treat diseases, including cell proliferation diseases and disorders such as cancer, particularly MYC-driven cancer. Compositions are described comprising a compound of formula (I), as well as pharmaceutical compositions or medicaments thereof. Also described are methods of use of such compositions to treat, prevent, or ameliorate diseases, including cell proliferation diseases and disorders such as cancer, in particular MYC-driven cancer. Compositions comprising conjugates and complexes of a compound of formula (I) are also described, which are also useful in the methods described herein. Methods are described comprising the use of a compound of formula (I), or pharmaceutical compositions thereof, for the reduction or inhibition of MYC expression or activity, and/or for achieving one or more desirable phenotypic outcomes such as, for example, decrease in cancer cell growth or proliferation, decrease in cancer cell viability, decrease in tumor volume (i.e., tumor regression), decrease in cancer metastasis, increase in animal or human survival, or other desired outcome with respect to particular phenotypes (e.g., body weight, metabolism, etc.). Related medicaments, kits, and methods of delivery of such compositions are described. Methods are also described for the development, manufacture, and/or synthesis of a compound of formula (I), as well as pharmaceutical compositions thereof. Furthermore, methods for diagnostics and testing comprising detecting MYC expression or activity levels, as well as compositions comprising kits for diagnostics and testing, are described.