DNA-templated synthesis for macrocyclic kinase inhibitors

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for discovering small molecules that modulate kinase enzyme activity are limited, particularly in generating biologically active macrocyclic compounds with high specificity and affinity, due to challenges in synthesizing macrocyclic structures and identifying effective candidates for clinical and research applications.

Innovation Solution

DNA-templated organic synthesis is used to translate DNA sequences into synthetic macrocycle libraries, enabling in vitro selection of compounds that modulate kinase enzyme activity, including the development of macrocyclic peptide-like structures that inhibit or activate specific kinases with high selectivity and potency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If combinatorial or diversity-oriented synthesis and high-throughput screening are used to discover small molecules, then a large number of compounds can be generated and screened, but the ability to generate biologically active macrocyclic compounds with high specificity and affinity is limited

Engineering Contradiction:

Improvenumber of compounds generated and screenedVSAvoidspecificity and affinity of macrocyclic compounds

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The patent changes the fundamental approach from random combinatorial synthesis to DNA-templated synthesis, where DNA base pairing provides precise spatial and temporal control over reactant assembly. This parameter change in the synthesis methodology enables the generation of macrocyclic compounds with high specificity and affinity while maintaining productivity through automated DNA-based library generation.

Inventive Principle:

Principle #35Parameter changes

2Ease of manufacture

If macrocyclic structures are synthesized traditionally, then linear analogs can be produced, but bioavailability, membrane permeability, and resistance to in vivo degradation are reduced

Engineering Contradiction:

Improvesynthesis of linear analogsVSAvoidbioavailability, membrane permeability, and resistance to degradation

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent replaces traditional chemical synthesis mechanisms with DNA-templated synthesis mechanisms. The DNA template acts as a molecular scaffold that directs the assembly of macrocyclic structures through base-pairing interactions, enabling the formation of rigid macrocyclic scaffolds that possess superior bioavailability, membrane permeability, and resistance to degradation compared to linear analogs.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Manufacturing precision

If DNA-templated synthesis is used to generate macrocycle libraries, then in vitro selection can identify compounds with high affinity, but the complexity of DNA template design and synthesis increases

Engineering Contradiction:

Improveaffinity and specificity of selected compoundsVSAvoidDNA template design and synthesis complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent segments the DNA template into modular components that can be independently designed and assembled. This segmentation allows for systematic optimization of template sequences and structures, reducing the overall complexity by breaking down the design process into manageable modules that can be standardized and reused across different macrocycle library preparations.

Inventive Principle:

Principle #1Segmentation

4Ease of operation

If traditional high-throughput screening is used, then screening can be performed with conventional methods, but the ability to selectively modulate kinase enzyme activity is limited

Engineering Contradiction:

Improveconventional screening methodsVSAvoidability to modulate kinase enzyme activity

Core Design Contradiction:

Ease of operationVSAdaptability or versatility

Solution Approach 1:

The patent creates a universal DNA-templated synthesis platform that can generate diverse macrocyclic libraries suitable for screening against multiple kinase targets. This universal approach allows the same methodology to be applied across different kinase families and disease indications, significantly enhancing the adaptability and versatility of the screening process while maintaining ease of operation through standardized protocols.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS8975232B2Macrocyclic kinase inhibitors and uses thereof

Publication Date: 2015.03.10 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

The present invention provides macrocyclic compounds of Formula (I): pharmaceutically acceptable salts thereof; and pharmaceutical compositions thereof, wherein R1, R2, R3, R4, RE, RF, RG, RH, RI, f, g, h, n, and m are as defined herein. The present invention further provides methods of synthesizing these macrocyclic compounds, and methods of their use and treatment. Certain aspects of the present invention relate to modulation of kinase activity, and in the treatment of kinase-associated diseases or disorders.