Selective PI3K Inhibitors for Isoform Specificity
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Solution Overview
Problem
There is a need for PI3K inhibitors that can selectively inhibit certain isoforms of class I PI3K, such as PI3K δ and/or PI3K γ, without substantially affecting the activity of PI3K β, to reduce side effects associated with unnecessary down-regulation of PI3K β activity and effectively address disease conditions mediated by PI3K δ/γ.
Innovation Solution
A compound of Formula I or Ib, which includes specific structural elements allowing for selective modulation of PI3K δ isoform over PI3K β isoform, with a ratio of selectivity greater than a factor of 10, is provided, enabling effective inhibition of PI3K δ while minimizing impact on PI3K β activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PI3K inhibitors are used to treat diseases mediated by PI3K δ/γ, then therapeutic effect is improved, but side effects occur due to down-regulation of PI3K β activity
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural features (such as particular substituents at defined positions in the molecular scaffold) that confer selective affinity for PI3K δ/γ isoforms while sparing PI3K β. This allows the same inhibitor molecule to exhibit different binding characteristics toward different kinase isoforms, achieving localized selectivity in its biological effect.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the inhibitor molecules (substituent types, positions, and configurations) to modulate isoform selectivity. By adjusting these chemical parameters, the invention optimizes the ratio of inhibition against PI3K δ/γ versus PI3K β, thereby improving therapeutic index.
2Reliability
If PI3K β activity is down-regulated, then certain disease conditions may be treated, but unnecessary side effects occur due to loss of PI3K β function
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural features (such as particular substituents at defined positions in the molecular scaffold) that confer selective affinity for PI3K δ/γ isoforms while sparing PI3K β. This allows the same inhibitor molecule to exhibit different binding characteristics toward different kinase isoforms, achieving localized selectivity in its biological effect.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the inhibitor molecules (substituent types, positions, and configurations) to modulate isoform selectivity. By adjusting these chemical parameters, the invention optimizes the ratio of inhibition against PI3K δ/γ versus PI3K β, thereby improving therapeutic index.
3Adaptability or versatility
If broad-spectrum PI3K inhibitors are used, then multiple disease conditions may be addressed, but selectivity against specific isoforms is reduced
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural features (such as particular substituents at defined positions in the molecular scaffold) that confer selective affinity for PI3K δ/γ isoforms while sparing PI3K β. This allows the same inhibitor molecule to exhibit different binding characteristics toward different kinase isoforms, achieving localized selectivity in its biological effect.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the inhibitor molecules (substituent types, positions, and configurations) to modulate isoform selectivity. By adjusting these chemical parameters, the invention optimizes the ratio of inhibition against PI3K δ/γ versus PI3K β, thereby improving therapeutic index.
Data Source
AI summary
Substituted isoquinolinone compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.