Fused Tricyclic mTOR Inhibitors for Dual Complex Targeting

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Solution Overview

Problem

There is a need for small-molecule compounds with desirable physiochemical properties that can effectively inhibit both mTORC1 and mTORC2 to treat cancer and other cellular proliferative diseases, as current inhibitors may not fully address the broader spectrum of antitumor activity by only targeting mTORC1.

Innovation Solution

Development of novel fused tricyclic derivatives that can inhibit mTOR kinase, specifically targeting both mTORC1 and mTORC2 complexes, with structures defined by a specific formula that includes various substituents and isotopic variations for enhanced therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If rapamycin is used to inhibit mTORC1, then partial inhibition of mTOR function is achieved, but complete inhibition of both mTORC1 and mTORC2 is not achieved, limiting antitumor activity

Engineering Contradiction:

Improveinhibition efficacyVSAvoidcomplex targeting capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies the universality principle by designing a single small molecule compound that performs multiple functions: it can inhibit both mTORC1 and mTORC2 complexes simultaneously. This multi-functional inhibitor addresses the limitation of rapamycin which only partially inhibits mTORC1, thereby achieving complete mTOR pathway inhibition with one agent.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent employs parameter changes by modifying the chemical structure to create novel fused tricyclic derivatives with optimized properties. These structural modifications enable the compounds to achieve desirable physiochemical properties while maintaining the ability to inhibit both mTORC1 and mTORC2, thus improving upon the limitations of existing inhibitors.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If small molecule inhibitors are designed to target both mTORC1 and mTORC2, then broader spectrum antitumor activity is achieved, but development complexity increases

Engineering Contradiction:

Improveantitumor activity spectrumVSAvoidmolecule structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the mTOR inhibition function into two distinct complex targets (mTORC1 and mTORC2) and designing a molecule that can address both. The fused tricyclic structure is segmented into specific rings and substituents that can interact with different binding sites, enabling dual complex inhibition through structured molecular design.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses composite materials principle by creating fused tricyclic compounds that combine multiple structural elements (different rings, substituents, and isotopic variations) into a single composite molecular structure. This composite approach allows the molecule to possess the necessary properties to inhibit both mTORC1 and mTORC2 while maintaining a defined chemical structure.

Inventive Principle:

Principle #40Composite materials

Data Source

PatentEP2621925B1Fused tricyclic inhibitors of mammalian target of rapamycin

Publication Date: 2017.06.21 MERCK SHARP & DOHME CORP

AI summary

This invention relates to novel fused tricyclic compounds that are inhibitors of mammalian Target of Rapamycin (mTOR) kinase, which is also known as FRAP, RAFT, RAPT or SEP, and are useful in the treatment of cellular proliferative diseases, for example cancer and other proliferative disorders.