Fused Pyrimidine PI3Kα Inhibitors with Allosteric Selectivity

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Solution Overview

Problem

Current kinase inhibitors face challenges in target selectivity, particularly for the PI3Kα isoform, and suffer from off-target toxicities and poor aqueous solubility, limiting their effectiveness in cancer treatment.

Innovation Solution

Development of fused pyrimidine compounds with saturated heterocyclic scaffolds that act as isoform-selective PI3Kα inhibitors, offering improved selectivity and solubility through specific synthetic processes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If ATP-competitive kinase inhibitors are used, then kinase inhibition activity is achieved, but target selectivity deteriorates

Engineering Contradiction:

Improvekinase inhibition activityVSAvoidtarget selectivity

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent changes the binding mechanism parameter from ATP-competitive to allosteric inhibition, targeting a distinct site on the PI3Kα enzyme. This parameter change enables isoform-selective inhibition of PI3Kα without affecting other PI3K isoforms, resolving the selectivity issue while maintaining potent kinase inhibition activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention targets a specific local region (allosteric site) on the PI3Kα enzyme rather than the general ATP binding site. This localized approach allows selective modulation of PI3Kα function without interfering with other kinase isoforms, achieving both high activity and selectivity

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If pan-PI3K inhibitors are used, then broad kinase coverage is achieved, but off-target toxicities increase

Engineering Contradiction:

Improvekinase coverageVSAvoidoff-target toxicities

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the specificity parameter from pan-PI3K inhibition to isoform-selective PI3Kα inhibition by targeting the unique allosteric site of PI3Kα. This enables selective coverage of only the desired isoform, preventing off-target effects on other PI3K isoforms while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention converts the structural similarity among PI3K isoforms (which causes cross-reactivity) into a benefit by exploiting the unique allosteric site architecture of PI3Kα. This allows selective targeting despite overall isoform similarity, achieving precise coverage without harmful off-target effects

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Reliability

If PI-103 is used as PI3K inhibitor, then multi-targeted inhibition is achieved, but aqueous solubility deteriorates

Engineering Contradiction:

Improvemulti-targeted inhibitionVSAvoidaqueous solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the chemical structure parameters of the inhibitor compound to improve aqueous solubility while maintaining multi-targeted inhibition capability. The novel fused pyrimidine core structure with specific substituents provides both the required pharmacological activity and enhanced solubility properties compared to PI-103

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3380476B1Fused pyrimidines as isoform selective phosphoinositide-3-kinase-alpha inhibitors and process for preparation thereof

Publication Date: 2020.09.30 COUNCIL OF SCI & IND RES

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AI summary

The present invention relates to fused pyrimidines of formulae I and II wherein, R1, R2 are as herein described. The present invention particularly relates to isoform selective PI3Kα inhibition and their medicinal use as anticancer agents.