ERAP1 Modulators for Controlled Neoantigen Presentation
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Solution Overview
Problem
Current cancer treatments, such as checkpoint inhibitor immunotherapies, are less effective in cancers with lower levels of neoantigens due to ERAP1's role in trimming peptides to suboptimal lengths for MHC Class I binding, and its over-trimming preventing antigen presentation.
Innovation Solution
Development of ERAP1 modulating compounds, including bis-aryl sulfonamide compounds, to alter antigen and neoantigen presentation, enhancing visibility of cancer cells to the immune system and potentially combining with existing immunotherapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitor immunotherapies are used, then cancer treatment is improved, but effectiveness is reduced in cancers with lower levels of neoantigens due to ERAP1 over-trimming
Solution Approach 1:
The patent converts the harmful effect of ERAP1 over-trimming into a benefit by developing compounds that selectively modulate ERAP1 activity. Instead of completely inhibiting ERAP1, the compounds fine-tune its trimming activity to prevent over-trimming of neoantigens while maintaining its beneficial antigen presentation function, thereby converting the enzyme's harmful overactivity into a controlled, beneficial process that enhances immunotherapy effectiveness
Solution Approach 2:
The patent applies parameter changes by modifying ERAP1's enzymatic activity level through small molecule compounds. The compounds alter the kinetic parameters of ERAP1, specifically reducing its excessive trimming activity while preserving its essential function. This parameter modulation allows the system to operate in an optimal range where antigen presentation is enhanced without complete loss of ERAP1 function
2Quantity of substance
If ERAP1 activity is completely inhibited, then neoantigen presentation is improved, but antigen presentation pathway is disrupted
Solution Approach 1:
The patent applies partial action by implementing incomplete inhibition of ERAP1 activity. Rather than completely blocking the enzyme, the compounds achieve partial modulation that is sufficient to prevent over-trimming of neoantigens while leaving enough ERAP1 activity intact to maintain normal antigen presentation pathways. This partial intervention strikes a balance between enhancing neoantigen visibility and preserving immune system functionality
Solution Approach 2:
Instead of using complete inhibition as the approach, the patent inverts the strategy by using selective modulation. Rather than asking 'how to stop ERAP1 completely,' the invention asks 'how to fine-tune ERAP1 activity,' leading to compounds that adjust the enzyme's function rather than eliminate it, thereby maintaining pathway reliability while improving neoantigen presentation
Data Source
AI summary
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, A compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, (I) wherein: Z is a group of formula: (II) wherein P and Q are each independently CR12R13; or one of P and Q is NR14 and the other is CR12R13; the group X—Y is —NHSO2— or —SO2NH—; R1 is H, CN or alkyl; R2 is selected from COOH and a tetrazolyl group; R3 is selected from H, Cl and alkyl; R4 is selected from H and halo; R5 is selected from H, alkyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R6 is H; R7 is selected from H, CN, haloalkyl, halo, SO2-alkyl, heteroaryl, SO2NR16R17, CONR10R11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R8 is selected from H, alkyl, haloalkyl and halo; R9 is H or halo; and R10, R11, R12, R13, R14, R16 and R17 are each independently H or alkyl; R15 is selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m and n are each independently 0, 1, 2 or 3. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.