Macrocyclic MCL-1 Inhibitors for Chemoresistance-Linked Cancer Survival

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Solution Overview

Problem

There is a need for compounds that inhibit the activity of the MCL-1 protein, which is implicated in mediating malignant cell survival in various cancers and contributing to chemoresistance, as existing therapies often fail to effectively target this protein.

Innovation Solution

Development of compounds of Formula (I) or their pharmaceutically acceptable salts, which selectively inhibit MCL-1 protein activity, thereby promoting apoptosis in cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing therapies are used to target MCL-1 protein, then cancer cell survival is maintained, but chemoresistance develops and treatment effectiveness decreases

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidchemoresistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs small molecule compounds with specific chemical structures (Formula I) that bind to MCL-1 protein, changing the molecular parameters of the protein's conformational state and preventing its anti-apoptotic function. This direct molecular intervention overcomes chemoresistance by targeting the specific protein rather than using conventional chemotherapy agents to which cells have developed resistance.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The MCL-1 inhibiting compounds act as intermediary molecules that bridge the therapeutic goal (inducing apoptosis) and the molecular target (MCL-1 protein). These compounds selectively bind to MCL-1, disrupting its interaction with pro-apoptotic proteins like BAX and BAK, thereby mediating cell death in cancer cells that would otherwise survive due to MCL-1 overexpression.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If MCL-1 protein activity is inhibited, then cancer cell death is enhanced, but selectivity against normal cells must be maintained

Engineering Contradiction:

Improvecancer cell death rateVSAvoidtoxicity to normal cells

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent achieves selective cancer cell death by exploiting the local quality difference between cancer and normal cells - specifically, the overexpression of MCL-1 in cancer cells. The compounds selectively target and inhibit MCL-1, which is present at high levels in cancer cells but at normal levels in healthy cells, thereby producing cytotoxic effects primarily in cancer cells while sparing normal tissue.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent utilizes the fact that cancer cells have excessive MCL-1 expression compared to normal cells. By inhibiting MCL-1 activity, the compounds create a partial disruption of the apoptotic balance that is sufficient to trigger cell death in cancer cells (which rely heavily on MCL-1 for survival) but insufficient to affect normal cells that have adequate apoptotic regulation through other BCL-2 family members.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS20250313572A1Macrocyclic MCL-1 inhibitors and methods of use

Publication Date: 2025.10.09 ABBVIE INC

AI summary

The present disclosure provides for compounds of Formula (I)wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).