Spirocyclohexane Mcl-1 Inhibitors for Apoptosis Induction

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Solution Overview

Problem

There is a high therapeutic need for compounds that inhibit the anti-apoptotic activity of the Mcl-1 protein, which is often overexpressed in various cancers and immune diseases, as existing BH3 mimetics have shown promise but are still under clinical investigation.

Innovation Solution

Development of potent selective Mcl-1 inhibitors of Formula (I) that exhibit strong binding affinity to the Mcl-1 receptor and induce apoptosis, offering potential therapeutic benefits for cancer, autoimmune diseases, and immune system disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing BH3 mimetics are used to inhibit Mcl-1 protein, then anti-apoptotic activity is reduced, but therapeutic efficacy is insufficient and clinical results are pending

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidclinical progress

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies the chemical structure of BH3 mimetics by introducing specific substituents at defined positions in the molecular framework, changing physical and chemical parameters to enhance binding affinity and selectivity for Mcl-1, thereby improving therapeutic efficacy while maintaining drug-like properties

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining heterocyclic cores with specific side chains and functional groups, forming a composite BH3 mimetic architecture that achieves superior Mcl-1 inhibition compared to simpler analogs, addressing the need for more effective therapeutic agents

Inventive Principle:

Principle #40Composite materials

2Reliability

If Mcl-1 protein is overexpressed in cancer cells, then cell survival is enhanced, but resistance to chemotherapy develops

Engineering Contradiction:

Improvecell survival controlVSAvoidchemoresistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent exploits the overexpression of Mcl-1 in cancer cells, which normally confers survival advantage and chemoresistance, by designing inhibitors that specifically target this overexpressed protein, converting the harmful overexpression into a therapeutic vulnerability that sensitizes cancer cells to chemotherapy

Inventive Principle:

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

Solution Approach 2:

The BH3 mimetic compounds act as intermediary molecules that disrupt the protective interaction between Mcl-1 and pro-apoptotic BH3-only proteins, freeing these pro-apoptotic proteins to trigger cell death pathways and overcome chemoresistance without directly damaging the cancer cell

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260001846A1Spirocyclohexane derivatives, pharmaceutical compositions containing them and their uses as Anti-apoptotic inhibitors

Publication Date: 2026.01.01 LES LAB SERVIER SA

AI summary

Compounds of Formula (I):wherein R1, R2, R3, R4 and are as defined in the description.Medicinal products containing the same which are useful in treating conditions requiring anti-apoptotic inhibitors.