Solid-State HIF Inhibitor Forms for Disrupting p300/CBP Binding
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Solution Overview
Problem
Current treatments for hypoxia-related pathologies, such as cancer and ischemic heart disease, are limited in effectively inhibiting the function of the hypoxia inducible factor 1 (HIF) transcription factor, which plays a critical role in hypoxic conditions.
Innovation Solution
Development of novel solid-state forms of the HIF inhibitor Compound 9 and its pharmaceutically acceptable salts, which bind to the CH1 domain of the transcription co-activator p300/CBP, preventing the assembly of critical co-activator proteins on the HIF transcription complex during hypoxia.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for hypoxia-related pathologies are used, then they are limited in effectively inhibiting HIF function, but no specific limitation is stated in terms of patent parameters
Solution Approach 1:
The patent applies parameter changes by developing novel solid-state forms of Compound 9 with specific crystalline structures (Forms 1-4 with distinct XRPD patterns). These solid-state modifications enhance the compound's solubility, stability, and bioavailability, thereby improving its effectiveness in inhibiting HIF function while maintaining a manageable treatment complexity
Solution Approach 2:
The patent creates composite pharmaceutical compositions containing Compound 9 in specific solid-state forms combined with pharmaceutically acceptable excipients. These composite materials optimize drug delivery and effectiveness for treating hypoxia-related pathologies while providing a structured approach that manages treatment complexity
2Reliability
If Compound 9 binds to the CH1 domain of p300/CBP to prevent co-activator assembly, then HIF activity is effectively inhibited, but the complexity of the molecular mechanism increases
Solution Approach 1:
The patent applies the extraction principle by isolating and targeting a specific component (the CH1 domain of p300/CBP) within the larger HIF transcription complex. By designing Compound 9 to specifically bind this domain, the invention effectively disrupts co-activator assembly and HIF activity without requiring complex multi-target mechanisms
Solution Approach 2:
The patent uses Compound 9 as an intermediary molecule that mediates the disruption between HIF and its co-activators. The compound acts as a molecular bridge that binds to the CH1 domain of p300/CBP, preventing the natural interaction between HIF and co-activators while maintaining a relatively simple single-molecule mechanism
Data Source
AI summary
The disclosure is directed to novel solid-state forms of Compound 9 and pharmaceutically acceptable salts of Compound 9, compositions comprising the same, and methods of using the same, including use in treating cancer, hypoxia related pathologies, disorders leading to ischemia, and non-cancerous angiogenic diseases.