Smac Mimetics Disrupt IAP Binding to Restore Caspase Activity

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Solution Overview

Problem

Cancer cells evade apoptosis through interactions with Inhibitor of Apoptosis Proteins (IAPs), making standard treatments ineffective due to resistance mechanisms.

Innovation Solution

Development of substituted 1,5-disubstituted (S)-3-amino-substituted 2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-ones that bind to the BIR2 and/or BIR3 regions of IAPs, such as XIAP and cIAP, to activate or reactivate the caspase cascade, thereby overcoming apoptosis resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If standard treatments (chemotherapeutics or radiation) are used, then cancer treatment is attempted, but cancer cells resist due to altered apoptotic pathways and IAP protein interactions

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidapoptosis resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces Smac mimetics as intermediary compounds that mediate between the apoptotic machinery and IAP proteins. These small molecule compounds mimic the endogenous Smac protein to displace IAP-caspase complexes, thereby restoring apoptosis in cancer cells that have developed resistance to standard treatments

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention creates synthetic copies of the Smac protein through small molecule design. These Smac mimetics replicate the key functional features of endogenous Smac (specifically the BIR-domain binding interface) to compete with IAP proteins for caspase binding, effectively copying the protective apoptotic signal that cancer cells have evaded

Inventive Principle:

Principle #26Copying

2Reliability

If IAP proteins bind to caspases, then apoptosis is inhibited and cancer cells survive, but this binding prevents caspase activation and therapeutic response

Engineering Contradiction:

Improveapoptotic pathway functionVSAvoidcaspase inhibition

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The Smac mimetics are designed to preemptively counteract the harmful IAP-caspase binding interaction. By introducing compounds that have higher affinity for IAP BIR domains than the endogenous IAP-caspase complex, the treatment prevents the inhibitory interaction from occurring or reverses it before it can block apoptosis

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The invention exploits the high binding affinity of IAP BIR domains for their ligands (both endogenous Smac and caspases) and converts this harmful binding capability into a beneficial therapeutic mechanism. The same structural features that enable IAPs to inhibit apoptosis are utilized by Smac mimetics to displace IAPs and restore caspase activity

Inventive Principle:

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

Data Source

PatentEP3071562B1Tetrahydro-benzodiazepinones

Publication Date: 2020.10.14 F HOFFMANN LA ROCHE & CO AG

AI summary

Disclosed are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W, X, Y, Z, R1, R2, R3, R4 and R5 are as described in this application, and methods of using said compounds in the treatment of cancer.