Allosteric AKT Inhibitors for Blocking HHT Vascular Malformations
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Solution Overview
Problem
Current treatments for Hereditary Hemorrhagic Telangiectasia (HHT) are ineffective and lack an acceptable safety profile, as existing PI3K/AKT/mTOR signaling inhibitors like Wortmannin and sirolimus fail to inhibit arteriovenous malformations in certain mouse models.
Innovation Solution
Development of a specific allosteric AKT inhibitor, represented by compound of formula (I), which targets the PI3K/AKT/mTOR signaling pathway to treat HHT, demonstrating an acceptable safety profile and effective prevention of vascular malformations at lower dosages than those used in oncology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan PI3K inhibitors like Wortmannin are used to treat HHT, then PI3K/AKT signaling is inhibited, but the treatment fails to inhibit AVM formation in certain mouse models and lacks acceptable safety profile
Solution Approach 1:
The patent applies local quality by developing an allosteric AKT inhibitor that specifically targets the AKT isoforms expressed in endothelial cells (AKT1 and AKT2) rather than using broad-spectrum pan-PI3K inhibitors. This localized targeting approach ensures effective inhibition of pathological angiogenesis in HHT while minimizing off-target effects on other cell types and physiological processes, thereby improving both effectiveness and safety profile
Solution Approach 2:
The patent employs parameter changes by modifying the inhibition strategy from pan-PI3K inhibition to selective allosteric AKT inhibition. This parameter change in the molecular target and mechanism of action allows for more precise control of the PI3K/AKT/mTOR pathway, achieving effective treatment of HHT vascular malformations while reducing harmful side effects associated with broad pathway inhibition
2Reliability
If mTOR inhibitors like sirolimus are used to treat HHT, then mTOR signaling is inhibited, but the treatment fails to block AVM formation in Eng-iKO model
Solution Approach 1:
The patent applies preliminary action by upstreaming the inhibition target from mTOR to AKT in the PI3K/AKT/mTOR signaling pathway. By inhibiting AKT allosterically upstream of mTOR, the treatment prevents downstream activation of mTOR and other AKT-dependent pathways, ensuring effective blockade of AVM formation in Eng-iKO models where单纯的mTOR inhibition fails
Solution Approach 2:
The patent uses an allosteric AKT inhibitor as an intermediary that modulates the PI3K/AKT/mTOR pathway more effectively than direct mTOR inhibition. This intermediary approach at the AKT level provides broader pathway control and adapts to different HHT mouse model pathologies, improving versatility across Eng-iKO, ALK1-iKO, and other HHT models
Data Source
AI summary
The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, for use in the treatment of Hereditary Hemorrhagic Telangiectasia (HHT).