Selective DPP9 Binding Compounds for Targeted Proteolysis
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Solution Overview
Problem
Current inhibitors for Dipeptidyl peptidase 9 (DPP9) lack selectivity, often targeting other DASH proteases like DPP8 and DPP4, and there is a need for compounds that can discriminate between DPP8 and 9, particularly for therapeutic and research applications, especially in cancer.
Innovation Solution
Development of DPP9 binding compounds with an isoindoline-aminoacyl-adamantyl basic structure that selectively inhibits DPP9, optionally incorporating an E3 ligase binding moiety to induce ubiquitination and intracellular proteolysis, and can function as specific probes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing DASH protease inhibitors are used, then DPP9 activity is inhibited, but selectivity is lost and other DASH proteases (DPP8, DPP4) are also inhibited
Solution Approach 1:
The patent applies local quality by introducing specific structural features (isoindoline ring, aminoacyl group, adamantyl group) at specific positions in the inhibitor molecule to create selective interactions with DPP9's active site. The isoindoline ring forms hydrogen bonds with Asp248 and Asp249 in DPP9, while the adamantyl group interacts with the S1 pocket, creating localized high-affinity binding sites that discriminate DPP9 from DPP8 and DPP4.
Solution Approach 2:
The patent employs asymmetry by creating an unsymmetric molecular structure where the isoindoline-aminoacyl-adamantyl groups are arranged in a specific asymmetric configuration. This asymmetric arrangement creates steric hindrance and specific geometric complementarity with DPP9's asymmetric active site cleft, preventing binding to the more symmetric DPP8 and DPP4 active sites.
2Reliability
If non-selective DPP9 inhibitors are used, then DPP9 function is blocked, but off-target effects on other proteases occur
Solution Approach 1:
The patent applies parameter changes by systematically varying key structural parameters of the inhibitor molecule - specifically the isoindoline aminoacyl adamantyl configuration and substituent groups (R1-R6, X, Y). By optimizing these molecular parameters, the compound achieves high affinity for DPP9 (IC50 in nanomolar range) while maintaining minimal activity against DPP8 and DPP4, thereby reducing off-target effects.
3Adaptability or versatility
If selective DPP9 inhibitors are developed, then therapeutic specificity is improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the inhibitor molecule into three distinct functional segments: (1) the isoindoline ring system that binds to the catalytic triad, (2) the aminoacyl group that forms hydrogen bonds with Asp248/249, and (3) the adamantyl group that occupies the S1 pocket. This segmentation allows each segment to be optimized independently for specific DPP9 interactions while maintaining overall molecular manageability.
Data Source
AI summary
The invention relates to new compounds of the general Formula (I), which are Dipeptidyl peptidase 9 (DPP9) enzyme inhibitors. The present invention further relates to specific compounds based on Formula (I) that binds to an E3 ligase and to DPP9 and induce proteolysis of DPP9. The invention also relates to specific DPP9 binding compounds comprising a probe moiety, according to formula (I). The present invention further relates to pharmaceutical compositions and their use thereof.