Non-peptidic Smac Mimetics for IAP Binding

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Solution Overview

Problem

Current cancer therapies face resistance due to defects in apoptosis machinery in cancer cells, particularly due to overexpression of Inhibitor of Apoptosis Proteins (IAPs) like XIAP, cIAP-1, and cIAP-2, which suppress apoptosis induced by chemotherapeutic agents and radiation.

Innovation Solution

Development of non-peptidic, homodimeric and heterodimeric small molecules that mimic the binding of Smac to XIAP, cIAP-1, and cIAP-2, disrupting their interaction with caspases and facilitating apoptosis, thereby overcoming the limitations of peptide-based IAP inhibitors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If peptide-based IAP inhibitors are used, then binding affinity to IAPs is achieved, but pharmacokinetic properties are insufficient and resistance develops

Engineering Contradiction:

Improvebinding affinityVSAvoidpharmacokinetic effectiveness

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the fundamental chemical parameters of the inhibitor by transitioning from peptide-based to non-peptidic small molecule structures. This parameter change enables optimization of both binding affinity and pharmacokinetic properties simultaneously, resolving the contradiction where peptide inhibitors achieved binding but failed in therapeutic effectiveness due to rapid clearance and resistance.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention employs composite molecular designs combining multiple functional moieties within single small molecule structures. These composite non-peptidic compounds integrate IAP-binding pharmacophores with pharmacokinetic enhancers, achieving both high affinity binding and improved therapeutic efficacy, thereby resolving the limitation of simple peptide inhibitors.

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If Smac mimetic compounds are designed, then IAP binding is achieved, but selectivity and potency against specific IAP family members is insufficient

Engineering Contradiction:

ImproveIAP binding capabilityVSAvoidselectivity and potency

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies local quality by designing IAP-specific binding moieties within the Smac mimetic structure. Different pharmacophores are optimized to target specific IAP family members (XIAP, cIAP-1, cIAP-2) with distinct binding affinities and selectivities, allowing the compound to adapt to different IAP targets while maintaining high potency against each specific target.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention incorporates dynamic conformational features in the Smac mimetic structure that enable adaptive binding to different IAP family members. The molecular structure can flex and adjust its conformation to optimize binding interactions with specific IAP targets, thereby achieving both versatility across IAP family members and high selectivity/potency for each individual target.

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS9730976B2Homo- and heterodimeric SMAC mimetic compounds as apoptosis inducers

Publication Date: 2017.08.15 BIONTECH SE

AI summary

The present invention relates to conformationally constrained homo- and heterodimeric mimetics of Smac with function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs), the invention also relates to the use of these compounds in therapy, wherein the induction of apoptotic cell death is beneficial, especially in the treatment of cancer, alone or in combination with other active ingredients.