Indolinone Kinase Inhibitors Targeting PLK4 and Aurora B

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Solution Overview

Problem

There is a need for effective protein kinase inhibitors, particularly for polo-like kinase 4 (PLK4), as PLK4 is overexpressed in certain cancers and current therapeutic agents are insufficient in addressing this need.

Innovation Solution

Development of indolinone compounds that act as potent kinase inhibitors, including PLK4 inhibitors, which are used in pharmaceutical compositions to treat cancer and inhibit Aurora B and/or PLK4.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutic agents are used, then treatment of cancer is attempted, but they are insufficient in addressing PLK4 overexpression

Engineering Contradiction:

Improveeffectiveness of cancer treatmentVSAvoidability to target PLK4

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs parameter changes by modifying the chemical structure of kinase inhibitors to specifically target PLK4. The indolinone compounds are designed with specific molecular parameters (substituents at positions 5, 6, and 7 of the indolinone core) that enable selective binding to PLK4's ATP-binding site, thereby changing the specificity parameter of the inhibitor to address PLK4 overexpression in cancer

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent segments the kinase inhibitor design into distinct structural components: a core indolinone structure with specific substituent patterns at positions 5, 6, and 7. This segmentation allows optimization of each region independently - the core structure provides kinase binding affinity while specific substituents provide PLK4 selectivity, resolving the contradiction between general cancer treatment capability and specific PLK4 targeting

Inventive Principle:

Principle #1Segmentation

2Reliability

If indolinone compounds are developed as PLK4 inhibitors, then potent anticancer activity is achieved, but complexity of drug development increases

Engineering Contradiction:

Improveanticancer activityVSAvoidcomplexity of compound structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The indolinone compound structure serves multiple functions simultaneously: the core indolinone structure provides kinase binding affinity, while specific substituents at positions 5, 6, and 7 provide PLK4 selectivity and enhanced anticancer activity. This multi-functionality within a single molecular framework achieves potent anticancer activity without proportionally increasing structural complexity

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent uses the indolinone compound as an intermediary molecule that mediates between the therapeutic goal (inhibiting PLK4 to treat cancer) and the molecular requirements (specific binding to PLK4's ATP site). The compound's structured design with defined substituents acts as a precise intermediary that translates the therapeutic objective into effective molecular interaction, achieving potent anticancer activity through targeted PLK4 inhibition

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS8765748B2Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer

Publication Date: 2014.07.01 UNIV HEALTH NETWORK

AI summary

The present invention is directed to a compound is represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The present invention is also directed to a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Also disclosed is a method of treating a subject having cancer, wherein the method comprises administering a therapeutically effective amount of a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof.