Rapamycin Analogs Selective mTORC1 Inhibition

Solution Overview

Problem

Current therapies targeting mTORC1 often inadvertently inhibit mTORC2, leading to undesirable side effects due to the lack of selectivity, particularly with chronic treatment, which affects metabolic processes and insulin signaling.

Innovation Solution

Development of novel rapamycin analogs with specific substitutions at the C-7 position, such as larger groups, that selectively inhibit mTORC1 without impacting mTORC2, thereby improving solubility and pharmacokinetics compared to traditional rapamycin.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If rapamycin is used to inhibit mTORC1, then cell growth and proliferation are suppressed, but mTORC2 activity is also inhibited leading to metabolic side effects

Engineering Contradiction:

ImprovemTORC1 inhibition efficacyVSAvoidmTORC2 inhibition side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making selective modifications at specific positions (C-7 and C-43) of the rapamycin molecule. By introducing larger groups at C-7 and specific substituents at C-43, the compound achieves differentiated binding characteristics that selectively inhibit mTORC1 while sparing mTORC2, thus resolving the contradiction between mTORC1 inhibition efficacy and mTORC2 inhibition side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying chemical parameters (substituent size, hydrophobicity, molecular weight) at specific positions of the rapamycin structure. These parameter modifications alter the compound's binding affinity and selectivity, enabling selective mTORC1 inhibition without mTORC2 inhibition, thereby eliminating the harmful side effects while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

2Duration of action of moving object

If chronic rapamycin treatment is administered, then mTORC1 inhibition is sustained, but mTORC2 assembly is blocked leading to prolonged side effects

Engineering Contradiction:

ImprovemTORC1 inhibition durationVSAvoidmTORC2 assembly blocking

Core Design Contradiction:

Duration of action of moving objectVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by making selective modifications at specific positions (C-7 and C-43) of the rapamycin molecule. By introducing larger groups at C-7 and specific substituents at C-43, the compound achieves differentiated binding characteristics that selectively inhibit mTORC1 while sparing mTORC2, thus resolving the contradiction between mTORC1 inhibition efficacy and mTORC2 inhibition side effects

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs the principle of using compounds with optimized pharmacokinetic properties that provide sustained mTORC1 inhibition without causing prolonged mTORC2 blocking. The modified rapamycin analogs are designed to achieve adequate inhibition duration through controlled metabolic clearance, avoiding the need for chronic accumulation that would otherwise block mTORC2 assembly

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Reliability

If traditional rapamycin is used, then mTORC1 inhibition is achieved, but solubility and pharmacokinetics are suboptimal

Engineering Contradiction:

ImprovemTORC1 inhibitionVSAvoidsolubility and pharmacokinetics

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs parameter changes by systematically varying chemical parameters (substituent size, hydrophobicity, molecular weight) at specific positions of the rapamycin structure. These parameter modifications alter the compound's binding affinity and selectivity, enabling selective mTORC1 inhibition without mTORC2 inhibition, thereby eliminating the harmful side effects while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies composite materials by creating hybrid molecular structures that combine the core rapamycin scaffold with optimized substituent groups. The composite structure integrates the essential mTORC1 binding pharmacophore with improved solubility-enhancing and pharmacokinetic optimization groups, achieving both therapeutic efficacy and improved drug properties

Inventive Principle:

Principle #40Composite materials

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

These compounds effectively inhibit mTORC1 while sparing mTORC2, reducing side effects and maintaining metabolic function, as demonstrated by prolonged selective inhibition in cellular assays and animal models.

Implementation Method 1

rapamycin binds to FK506-binding protein of 12 kDa (FKBP12) and interacts with the FKBP12-rapamycin binding domain (FRB) of mTOR

Methodology Applied

Scientific EffectMolecular binding:

Implementation Method 2

this complex binds and specifically acts as an allosteric inhibitor of mammalian TOR (mTOR) complex 1 (mTORC1)

Methodology Applied

Scientific EffectAllosteric inhibition:

Data Source

PatentUS20240173305A1Rapamycin analogs and uses thereof

Publication Date: 2024.05.30 JANSSEN PHARMA NV

AI summary

The present invention provides compounds, compositions thereof, and methods of using the same.