DCN-1 Modulating Compounds for Fetal Hemoglobin Induction
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Solution Overview
Problem
There is a need for therapeutic agents and methods to treat hemoglobin-related disorders such as sickle cell disorders and thalassemia, which affect hemoglobin production and cause significant morbidity and mortality.
Innovation Solution
Development of compounds that modulate DCN-1, a protein involved in the neddylation pathway, to induce fetal hemoglobin production, thereby addressing the underlying genetic defects in these disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional hemoglobin-targeted therapies are used, then adult hemoglobin production is suppressed, but fetal hemoglobin induction is insufficient to achieve therapeutic effect
Solution Approach 1:
The patent uses DCN-1 as an intermediary target to indirectly induce fetal hemoglobin production. Instead of directly targeting hemoglobin synthesis pathways, the compounds modulate DCN-1 protein levels, which in turn activates fetal hemoglobin expression through the neddylation pathway, achieving therapeutic effect with higher reliability
Solution Approach 2:
The invention changes the therapeutic parameter from direct hemoglobin suppression to DCN-1 modulation. By altering the molecular target from hemoglobin itself to the regulatory protein DCN-1, the therapy achieves more effective fetal hemoglobin induction while maintaining adult hemoglobin function
2Quantity of substance
If DCN-1 is completely inhibited to induce fetal hemoglobin, then fetal hemoglobin production increases, but normal cullin neddylation function is disrupted
Solution Approach 1:
The compounds achieve partial inhibition of DCN-1 function rather than complete blockade. This partial modulation is sufficient to induce fetal hemoglobin while preserving enough DCN-1 activity to maintain normal cullin neddylation and proteasomal function, avoiding the harmful effects of complete inhibition
Data Source
AI summary
The present disclosure provides DCN-1 modulating compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and their use for treating sickle cell disorders, diseases, and conditions. Such compounds are of Formula I:or a pharmaceutically acceptable salt thereof.