BCL-2 Inhibitor Combination to Overcome AML Resistance

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Solution Overview

Problem

Existing BCL-2 inhibitor monotherapies and combinations face resistance issues, particularly due to upregulation of BCL-2 family antiapoptotic proteins like BCL-XL and MCL-1, limiting their effectiveness in treating cancers such as AML.

Innovation Solution

Combining a BCL-2 inhibitor, such as Venetoclax, with SEL24/MEN1703, a dual pan-PIM/FLT3 inhibitor, to overcome resistance and enhance therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If BCL-2 inhibitor monotherapy is used, then safety is improved, but antileukemic activity is insufficient

Engineering Contradiction:

ImprovesafetyVSAvoidantileukemic activity

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent combines BCL-2 inhibitor with SEL24/MEN1703 (a dual pan-PIM/FLT3 inhibitor) to create a combination therapy that achieves both safety and antileukemic activity. The combination allows the BCL-2 inhibitor to be used at lower doses (reducing toxicity) while SEL24/MEN1703 provides additional antileukemic effect through PIM and FLT3 inhibition, thereby resolving the contradiction between safety and activity.

Inventive Principle:

Principle #5Merging (Combining)

2Productivity

If BCL-2 inhibitor combinations are used to enhance activity, then antileukemic activity is improved, but resistance develops due to upregulation of BCL-2 family antiapoptotic proteins

Engineering Contradiction:

Improveantileukemic activityVSAvoidresistance

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent converts the harmful resistance mechanism into a beneficial effect by using SEL24/MEN1703 to inhibit PIM kinases. PIM kinase inhibition prevents the phosphorylation and stabilization of BCL-XL and MCL-1, thereby blocking the resistance pathway that would normally be activated in response to BCL-2 inhibition. This transforms the potential harm of resistance into a benefit by preemptively blocking the resistance mechanism.

Inventive Principle:

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

Solution Approach 2:

The patent changes the therapeutic parameter from single-target BCL-2 inhibition to multi-target inhibition involving BCL-2, PIM kinases, and FLT3. By adding SEL24/MEN1703 which targets PIM and FLT3, the combination alters the mechanism of action to prevent resistance development while maintaining or enhancing antileukemic activity.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If higher doses of BCL-2 inhibitor are used to overcome resistance, then antileukemic activity is improved, but toxicity increases

Engineering Contradiction:

Improveantileukemic activityVSAvoidtoxicity

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent combines BCL-2 inhibitor with SEL24/MEN1703 to achieve synergistic antileukemic activity. This combination allows the BCL-2 inhibitor to be used at lower, better-tolerated doses while SEL24/MEN1703 contributes additional antileukemic effect through PIM and FLT3 inhibition, thereby maintaining high activity without increasing toxicity.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20260034116A1Cancer combination therapy including a BCL-2 inhibitor

Publication Date: 2026.02.05 RYVU THERAPEUTICS SA

AI summary

The present invention is inter alia concerned with a combination of (i) a BCL-2 inhibitor and (ii) SEL24/MEN1703 for use as medicament, preferably for use in the treatment of a patient suffering from cancer. The present invention is also concerned with a kit of dosage forms comprising (i) a dosage form comprising a BCL-2 inhibitor and (ii) a dosage form comprising SEL24/MEN1703; as well as dosage form comprising (i) a BCL-2 inhibitor and (ii) SEL24/MEN1703.