Quinazolinone BRAF Inhibitors With Reduced MAPK Paradoxical Activation

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Solution Overview

Problem

Current BRAF inhibitors for treating BRAFV600E-positive melanoma face rapid drug resistance and paradoxical activation of the MAPK signaling pathway, leading to secondary tumor growth and resistance acquisition.

Innovation Solution

Development of a novel BRAF inhibitor that modulates BRAF activity with reduced paradoxical activation of the MAPK signaling pathway, maintaining high potency against BRAFV600E-driven tumors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) are used to treat BRAFV600E-positive melanoma, then therapeutic efficacy is achieved, but rapid drug resistance develops and paradoxical activation of MAPK signaling occurs

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidduration of therapeutic benefit

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent modifies the chemical structure parameters of BRAF inhibitors by introducing specific substituents at the R1 position (cycloalkyl, heterocycloalkyl, aryl, or alkyl groups) to alter the binding characteristics and conformational effects on BRAF, thereby reducing paradoxical activation while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces a novel compound structure as an intermediary that binds to BRAF in a way that prevents dimerization-induced paradoxical activation, serving as a mediator between the drug and the target to achieve selective inhibition without the harmful paradoxical effect

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If conventional BRAF inhibitors are used, then BRAFV600E-driven tumors are targeted, but paradoxical activation of MAPK signaling pathway occurs leading to secondary tumor growth

Engineering Contradiction:

Improvepotency against BRAFV600EVSAvoidparadoxical MAPK activation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality modification by introducing specific functional groups at the R1 position of the quinazolinone core structure, creating localized chemical modifications that selectively influence the binding mode and conformational effects on BRAF without affecting the core inhibitory mechanism

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent inverts the conventional approach by designing an inhibitor that specifically prevents the dimerization-induced active conformation rather than simply blocking the ATP binding site, thereby inverting the mechanism of action to avoid paradoxical activation while maintaining inhibition of oncogenic BRAF

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentEP4263518B1New quinazolinone derivatives

Publication Date: 2026.04.01 F HOFFMANN LA ROCHE & CO AG

AI summary

The invention relates to a compound of formula (I) wherein A, L, R1, R2, R3 and R4 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.