Bcl-2 Functional Conversion by Small Molecules to Trigger Apoptosis

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Solution Overview

Problem

Existing cancer therapies targeting Bcl-2 family proteins face resistance due to upregulation of anti-apoptotic proteins, necessitating a need for agents that can selectively convert Bcl-2 from an anti-apoptotic to a pro-apoptotic form to induce apoptosis in Bcl-2 overexpressing tumors.

Innovation Solution

Development of small molecule mimics of NuBCP-9 peptide or methotrexate analogs that expose the BH3 domain of Bcl-2, converting it into a pro-apoptotic protein and activating the intrinsic apoptosis pathway.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule inhibitors are used to neutralize anti-apoptotic Bcl-2 members, then pro-apoptotic members can induce cell death in cancer cells, but cancer cells upregulate other anti-apoptotic Bcl-2 or non-Bcl-2 family proteins resulting in therapeutic resistance

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtherapeutic resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of inhibiting Bcl-2 to promote apoptosis, the invention uses small molecules to convert Bcl-2 into a pro-apoptotic protein by exposing its BH3 domain. This inverted approach transforms the anti-apoptotic protein into a cell-death-inducing agent, eliminating the need to overcome compensatory upregulation of other anti-apoptotic proteins that causes resistance to conventional inhibitors

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention changes the functional state of Bcl-2 from anti-apoptotic to pro-apoptotic through small molecule binding. This parameter change in protein function is achieved by exposing the BH3 domain, fundamentally altering Bcl-2's role in cell survival and overcoming the limitations of inhibition-based approaches

Inventive Principle:

Principle #35Parameter changes

2Reliability

If Bcl-2 inhibitors are used to treat cancer, then cell death can be induced in Bcl-2 dependent tumors, but the treatment lacks selectivity against normal cells with lower Bcl-2 expression

Engineering Contradiction:

Improvecancer cell killingVSAvoidtoxicity to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention exploits the local quality difference in Bcl-2 expression levels between cancer cells and normal cells. By designing small molecules that specifically convert Bcl-2 to pro-apoptotic form, the therapy achieves selective cell death in Bcl-2 overexpressing tumors while sparing normal cells with lower Bcl-2 expression, thus improving the therapeutic window

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12370169B2Small molecule Bcl-2 functional converters as cancer therapeutics

Publication Date: 2025.07.29 THE STATE OF OREGON ACTING BY & THROUGH THE OREGON STATE BOARD OF HIGHER EDUCATION ON BEHALF OF OREGON STATE UNIV

AI summary

Methods for inducing growth inhibition or apoptosis of Bcl-2-expressing cells and treatments of Bcl-2 expressing cancers are provided. Additionally, assays for agents that can induce apoptosis of Bcl-2 expressing cells are disclosed.