Mcl-1 Inhibitor Compounds Overcoming Cancer Drug Resistance

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Solution Overview

Problem

Mcl-1, an anti-apoptotic protein, is frequently amplified in cancers and confers drug resistance, making it a challenging target for cancer therapy.

Innovation Solution

Development of 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo compounds and their pharmaceutically acceptable salts, which inhibit Mcl-1, potentially overcoming drug resistance in cancer treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Mcl-1 is targeted for inhibition, then apoptosis induction in tumor cells is improved, but drug resistance mechanisms may worsen treatment efficacy

Engineering Contradiction:

Improveapoptosis induction efficacyVSAvoiddrug resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs parameter changes by developing compounds with specific molecular structures (Formula I with varying R1-R6 substituents) that optimize Mcl-1 binding affinity. By systematically modifying chemical parameters such as substituent groups, stereochemistry, and molecular weight, the invention achieves enhanced apoptosis induction while overcoming drug resistance mechanisms in tumor cells.

Inventive Principle:

Principle #35Parameter changes

2Measurement precision

If complex multi-cyclic compound structures are developed to inhibit Mcl-1, then binding specificity is improved, but manufacturing complexity increases

Engineering Contradiction:

Improvebinding specificityVSAvoidcompound synthesis

Core Design Contradiction:

Measurement precisionVSEase of manufacture

Solution Approach 1:

The patent applies segmentation by dividing the complex multi-cyclic compound into modular building blocks with specific stereochemical centers and ring systems. The core structure consists of fused cyclohexane and cyclopentane rings with defined stereocenters, allowing systematic synthesis through stepwise assembly of precursor molecules rather than attempting to construct the entire complex structure in one step.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention manages manufacturing complexity through parameter changes by optimizing key structural parameters such as molecular weight (500-1000 Da), logP values, and stereochemical configurations. These controlled parameter variations maintain binding specificity while facilitating practical synthesis through established organic chemistry methods for constructing polycyclic frameworks.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11472816B2Mcl-1 inhibitors and methods of use thereof

Publication Date: 2022.10.18 ASTRAZENECA AB

AI summary

Disclosed is a compound which is 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid (Formula I)and enantiomers and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions of 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.14,7.011,15.016,21.020,24.030,35]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid, and enantiomers and pharmaceutically acceptable salts thereof, and methods of treating cancer with such compounds and compositions.