Reversible BTK Inhibitor Compounds for C481 Resistance and Selectivity

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Solution Overview

Problem

Existing BTK inhibitors face challenges such as secondary resistance due to mutations like C481S, C481Y, C481R, C481F, lack of selectivity for BTK over ITK and EGFR, gastrointestinal side effects, and limited efficacy against cancer treatments with emerging resistance.

Innovation Solution

Development of reversible BTK inhibitors with high selectivity for BTK inhibition and low EGFR inhibition, designed to target the C481 mutations, and have a favorable pharmacokinetic profile with reduced cytotoxicity and safe metabolites.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If irreversible BTK inhibitors like ibrutinib are used to treat B-cell malignancies, then therapeutic efficacy is improved, but secondary resistance develops due to C481 mutations

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidresistance mutations

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent changes the binding mode parameter from irreversible covalent binding to reversible non-covalent binding, allowing the inhibitor to maintain efficacy while avoiding the resistance mechanism that targets covalent bond formation at C481

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces an alternative binding mechanism that mediates inhibition through reversible interactions with BTK residues, bypassing the C481 cysteine target that mediates resistance to irreversible inhibitors

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If BTK inhibitors with high BTK inhibition are developed, then therapeutic efficacy is improved, but EGFR inhibition increases causing gastrointestinal side effects

Engineering Contradiction:

ImproveBTK inhibition efficacyVSAvoidgastrointestinal side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing the inhibitor to specifically interact with unique structural features of BTK's ATP binding site, creating high selectivity for BTK over EGFR and other kinases, thereby achieving high BTK inhibition without EGFR-mediated gastrointestinal side effects

Inventive Principle:

Principle #3Local quality

3Reliability

If irreversible BTK inhibitors are used to achieve strong BTK inhibition, then therapeutic effect is improved, but selectivity over ITK decreases

Engineering Contradiction:

ImproveBTK inhibition strengthVSAvoidselectivity for BTK over ITK

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent exploits local structural differences between BTK and ITK ATP binding sites to create an inhibitor with high selectivity, using reversible binding to distinguish between the two kinases while maintaining strong inhibition of BTK

Inventive Principle:

Principle #3Local quality

4Reliability

If covalent reversible BTK inhibitors targeting C481 are used, then BTK inhibition is improved, but resistance mutations like C481S, C481Y, C481R, C481F emerge

Engineering Contradiction:

ImproveBTK inhibitionVSAvoidresistance to mutations

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent fundamentally changes the binding parameter from covalent to reversible non-covalent interaction, eliminating dependence on the C481 cysteine residue and thereby preventing resistance mutations at this position

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3782994B1Compounds useful as kinase inhibitors

Publication Date: 2025.07.16 LOXO ONCOLOGY INC

AI summary

This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.