SMAC Mimetics Antagonize cIAP1 and XIAP to Induce Apoptosis

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Solution Overview

Problem

Current cancer therapies face resistance due to cancer cells' inability to undergo apoptosis, primarily attributed to over-expression of IAPs like cIAP1 and cIAP2, which inhibit the apoptosis process, leading to treatment challenges.

Innovation Solution

Development of a SMAC mimetic compound that selectively antagonizes cIAP1 and XIAP, promoting apoptosis by mimicking the action of SMAC protein to overcome IAP inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemotherapy, radiation therapy, or immunotherapy is used to treat cancer, then cancer cell death is induced indirectly, but treatment resistance occurs due to defects in the apoptosis mechanism

Engineering Contradiction:

Improvetreatment efficacyVSAvoidapoptosis mechanism function

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent uses SMAC mimetic compounds as intermediaries to bridge the gap between therapeutic agents and cancer cells. These compounds mimic the endogenous SMAC protein to directly interact with and inhibit IAPs, thereby mediating the apoptosis induction process that conventional therapies cannot achieve due to IAP overexpression

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention creates synthetic copies of the natural SMAC protein through small molecule mimetics. These copied structures retain the key functional property of binding to IAPs (specifically cIAP1, cIAP2, and XIAP) while providing enhanced stability and pharmacological properties for therapeutic use

Inventive Principle:

Principle #26Copying

2Strength

If IAPs are over-expressed in cancer cells, then apoptosis is inhibited and cell survival is maintained, but resistance to conventional therapies develops

Engineering Contradiction:

Improvecell survival capabilityVSAvoidtreatment responsiveness

Core Design Contradiction:

StrengthVSReliability

Solution Approach 1:

The patent applies preliminary anti-action by pre-treating cancer cells with SMAC mimetic compounds that bind to and inhibit IAPs before conventional therapy is administered. This preliminary inhibition of the anti-apoptotic machinery sensitizes cancer cells to subsequent therapeutic interventions, preventing the development of resistance

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The invention converts the harmful overexpression of IAPs into a beneficial therapeutic target. By specifically designing compounds that recognize and bind to the overexpressed IAPs in cancer cells, the therapy exploits the very mechanism that causes resistance (IAP overexpression) to deliver selective cytotoxicity to cancer cells while sparing normal cells

Inventive Principle:

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

3Reliability

If peptidic IAP inhibitors are used to inhibit apoptosis, then IAP function is blocked, but selectivity and potency are limited

Engineering Contradiction:

ImproveIAP inhibition capabilityVSAvoiddrug development complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent fundamentally changes the physical and chemical parameters of IAP inhibitors by transitioning from large, flexible peptidic structures to small, rigid non-peptidic molecules. This parameter change improves pharmacokinetic properties, enhances brain penetration, increases metabolic stability, and simplifies manufacturing while maintaining or improving IAP inhibition potency and selectivity

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3712162B1SMAC mimetics used as IAP inhibitors and use thereof

Publication Date: 2022.08.24 CHIA TAI TIANQING PHARMA GRP CO LTD

AI summary

Disclosed are a class of SMAC mimetics used as IAP inhibitors, and in particular disclosed are compounds as shown in formula (I), isomers thereof, and pharmaceutically acceptable salts thereof. The IAP inhibitors are drugs for treating cancers, in particular breast cancer.