BTK Occupancy Assay Using Specific Probe Compounds

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Solution Overview

Problem

Current methods lack a reliable and efficient way to measure the occupancy of Bruton's Tyrosine Kinase (BTK) by BTK inhibitors, which is crucial for optimizing drug dosage and evaluating therapeutic efficacy in treating autoimmune and inflammatory diseases.

Innovation Solution

Development of specific probe compounds that bind to BTK, allowing for the determination of the percentage of BTK inhibition by measuring the occupancy of BTK in biological samples, thereby providing a pharmacodynamic readout of the inhibitor's effect.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If current methods are used to measure BTK occupancy, then the assessment of inhibitor efficacy is insufficient, but the reliability and efficiency of measurement is lacking

Engineering Contradiction:

ImproveBTK occupancy measurement accuracyVSAvoidmeasurement reliability

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent employs probe compounds as intermediary molecules that specifically bind to BTK with high affinity. These probes serve as mediators between the BTK inhibitor and the detection system, enabling indirect but reliable measurement of BTK occupancy through the probe's binding status, thereby resolving the contradiction between measurement precision and reliability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention utilizes changes in binding parameters (affinity, specificity) of the probe compounds to BTK to detect occupancy levels. By measuring the presence or absence of probe binding under controlled conditions, the system transforms the unobservable parameter of inhibitor occupancy into a measurable parameter through parameter changes in the probe-BTK interaction

Inventive Principle:

Principle #35Parameter changes

2Productivity

If no specific probe compounds are used, then the assessment of BTK inhibition is indirect, but the efficiency of determining occupancy is reduced

Engineering Contradiction:

Improveoccupancy determination efficiencyVSAvoidinhibitor effect assessment accuracy

Core Design Contradiction:

ProductivityVSMeasurement precision

Solution Approach 1:

The probe compounds are pre-designed and pre-characterized with specific binding properties to BTK before the actual occupancy measurement. This preliminary preparation of highly specific probes enables direct and efficient measurement of inhibitor occupancy without requiring complex indirect assessment methods, thereby improving both productivity and measurement precision

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent replaces indirect mechanical or biochemical assay systems with a more efficient probe-based detection system. The probe compounds directly report BTK occupancy status through their binding properties, substituting complex multi-step measurement protocols with a streamlined approach that enhances both efficiency and precision

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

Enables accurate assessment of BTK inhibitor occupancy, guiding optimal dosage selection and treatment efficacy, facilitating better clinical outcomes for autoimmune and inflammatory disease management.

Implementation Method 1

contacting a sample comprising a mixture of BTK kinase and a BTK inhibitor compound, with a probe to form a probe-bound kinase

Methodology Applied

Scientific EffectBinding:

Data Source

PatentUS10012650B2Assays for BTK inhibitors

Publication Date: 2018.07.03 MERCK PATENT GMBH

AI summary

The present invention relates to BTK occupancy assays.