AKR1C3-Dependent KARS Inhibitor Dosing for Biomarker-Selected Cancers
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Solution Overview
Problem
Current methods lack the ability to accurately identify subjects for treatment with tricyclic AKR1C3-dependent KARS inhibitors and determine appropriate dosages for treating cancers with genetic alterations in the NFE2L2/KEAP1 pathway, such as NFE2L2/KEAP1 mutated cancers, breast cancers, and prostate cancers.
Innovation Solution
Methods are developed to identify subjects in need of treatment with tricyclic AKR1C3-dependent KARS inhibitors by determining elevated levels of AKR1C3 biomarkers or detecting somatic mutations in NFE2L2, KEAP1, or CUL3 genes, and administering an effective amount of the inhibitor compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods are used for identifying subjects and determining dosages, then treatment can be provided, but accurate identification and appropriate dosage determination cannot be achieved
Solution Approach 1:
The patent performs preliminary identification of subjects with NFE2L2/KEAP1 pathway alterations and AKR1C3 overexpression before treatment initiation. This preliminary action ensures that only appropriate candidates receive the therapy, improving both identification accuracy and treatment reliability by preventing inappropriate use of the inhibitor
Solution Approach 2:
The patent establishes feedback mechanisms through monitoring AKR1C3 biomarker levels and genetic alterations during treatment. This feedback allows for real-time assessment of treatment response and enables dosage adjustments to maintain therapeutic efficacy while minimizing toxicity, thereby improving treatment reliability
2Adaptability or versatility
If a selective therapeutic approach targeting NFE2L2/KEAP1 mutated cancers is implemented, then treatment specificity is improved, but the complexity of identifying appropriate subjects increases
Solution Approach 1:
The patent segments the identification process into distinct steps: first detecting NFE2L2/KEAP1 pathway alterations, then assessing AKR1C3 overexpression levels. This segmentation breaks down the complex identification task into manageable components, making the process more systematic and less overwhelming while maintaining high selectivity
Solution Approach 2:
The patent uses AKR1C3 biomarker levels as an intermediary indicator to bridge the gap between genetic alterations and treatment response. Rather than directly measuring complex genetic pathways, the assay measures the downstream biomarker AKR1C3, which serves as a practical mediator for identifying suitable candidates and monitoring treatment efficacy
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 methods enable precise identification and treatment of subjects with tricyclic AKR1C3-dependent KARS inhibitors, targeting cancers with genetic alterations in the NFE2L2/KEAP1 pathway, thereby providing a selective therapeutic approach.
Implementation Method 1
AKR1C3 (also named type 2 3α(17β)-hydroxysteroid dehydrogenase) is an NADP(H)-dependent ketosteroid reductase, a member of the aldo-keto reductase (AKR) superfamily
Implementation Method 2
AKR1C3-dependent KARS inhibitors... Tricyclic ketone compounds that get converted to lysine t-RNA synthetase (KARS) inhibitors by AKR1C3 in the presence of NADPH
Data Source
AI summary
The present invention relates to methods of identifying a subject for treatment with or treating a subject with a tricyclic AKR1C3 dependent KARS inhibitor of formula (I), or a pharmaceutically acceptable salt thereof. The methods may comprise determining in a subject sample a level of at least one of the following biomarkers: AKR1C3, NFE2L2, KEAP1, or CUL3, wherein an elevated level of the biomarker identifies the subject as being in need of treatment; or detecting in a subject sample a somatic mutation in at least one of the following genes: NFE2L2, KEAP1, or CUL3, wherein detecting the somatic mutation identifies the subject as being in need of treatment.