Bivalent Smac Mimetics for IAP Inhibition

Solution Overview

Problem

Current cancer therapies face resistance due to cancer cells' defects in apoptosis machinery, leading to increased resistance to chemotherapy and radiation, and there is a need for potent, non-peptide inhibitors of Inhibitors of Apoptosis Proteins (IAPs) that can effectively induce apoptosis in cancer cells.

Innovation Solution

Development of bivalent Smac mimetics that bind to XIAP, cIAP1, and cIAP2 with high affinity, concurrently targeting both BIR2 and BIR3 domains to inhibit IAP protein activity, thereby sensitizing cancer cells to apoptosis inducers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If peptide-based inhibitors are used to target IAP proteins, then the ability to induce apoptosis in cancer cells is improved, but cell permeability and in vivo stability deteriorate

Engineering Contradiction:

Improveability to induce apoptosisVSAvoidcell permeability

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent replaces peptide-based inhibitors with small molecule compounds that mimic the Smac protein structure. This substitution transitions from a biological macromolecule system to a small molecule chemical system, achieving both high apoptotic activity and improved cell permeability without requiring carrier peptides.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent modifies molecular parameters by designing small molecule Smac mimetics with specific structural features (bicyclic core, substituted phenyl groups, carbonyl and hydroxyl functional groups) that optimize both biological activity and pharmacological properties including cell permeability and metabolic stability.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If peptide-based inhibitors are used to target IAP proteins, then the ability to induce apoptosis in cancer cells is improved, but in vivo stability deteriorates

Engineering Contradiction:

Improveability to induce apoptosisVSAvoidin vivo stability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent replaces peptide-based inhibitors with small molecule compounds that mimic the Smac protein structure. This substitution transitions from a biological macromolecule system to a small molecule chemical system, achieving both high apoptotic activity and improved cell permeability without requiring carrier peptides.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent modifies molecular parameters by designing small molecule Smac mimetics with specific structural features (bicyclic core, substituted phenyl groups, carbonyl and hydroxyl functional groups) that optimize both biological activity and pharmacological properties including cell permeability and metabolic stability.

Inventive Principle:

Principle #35Parameter changes

3Device complexity

If monovalent Smac mimetics are used, then the structural simplicity is maintained, but the potency in inhibiting IAP proteins deteriorates

Engineering Contradiction:

Improvemolecular structure complexityVSAvoidpotency in inhibiting IAP proteins

Core Design Contradiction:

Device complexityVSReliability

Solution Approach 1:

The patent merges two Smac-binding units into a single bivalent molecule, allowing simultaneous interaction with multiple IAP protein domains (BIR2 and BIR3). This combining approach dramatically enhances inhibitory potency while maintaining a relatively compact molecular structure.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The bivalent Smac mimetic is designed to interact with multiple IAP family members (XIAP, cIAP1, cIAP2) through its dual binding units, providing universal inhibition across the IAP protein family with high potency.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP2888265B1Bivalent inhibitors of IAP proteins and therapeutic methods using the same

Publication Date: 2017.10.11 THE RGT UNIV OF MICHIGAN

Figure 1

AI summary

Inhibitors of IAP proteins and compositions containing the same are disclosed. Methods of using the IAP protein inhibitors in the treatment of diseases and conditions wherein inhibition of IAP proteins provides a benefit, like cancers, also are disclosed.