PSMA-Binding Glutamate-Urea-Lysine Compounds for Tumor Penetration
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Solution Overview
Problem
Current therapies for prostate cancer, particularly relapsing and metastatic androgen-independent prostate cancer, lack effective methods for visualization and targeted treatment, with existing monoclonal antibodies showing limited clinical success due to low permeability in solid tumors.
Innovation Solution
Development of glutamate-urea-lysine PSMA-binding moieties that act as targeting agents, incorporating radiolabels through prosthetic groups, allowing for diagnostic and therapeutic applications in prostate cancer treatment by binding to prostate-specific membrane antigen (PSMA).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to target PSMA in prostate cancer, then specific binding to PSMA is achieved, but permeability in solid tumors is low
Solution Approach 1:
The patent segments the monoclonal antibody into a smaller molecular mimicry compound that retains PSMA binding capability. This segmentation allows the targeting agent to penetrate solid tumors more effectively while maintaining specific binding to PSMA, resolving the contradiction between binding reliability and tumor permeability.
Solution Approach 2:
The invention extracts the essential PSMA-binding function from the large monoclonal antibody structure and implements it in a smaller molecular mimicry framework. This extraction enables the agent to achieve both specific PSMA binding and improved permeability through solid tumor tissue.
2Adaptability or versatility
If radiolabels are incorporated into targeting compounds, then visualization and targeted treatment are enabled, but molecular weight increases
Solution Approach 1:
The patent creates a universal molecular mimicry platform that can accommodate various radiolabels and prosthetic groups while maintaining low molecular weight. This multi-functional design enables both diagnostic imaging and targeted therapy capabilities without significantly increasing the core molecular weight, as the radiolabels are attached as modular components rather than integral structural elements.
Data Source
AI summary
Compounds of Formula (Ia)wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)pY is C(O), O, NR′, S, S(O)2, C(O)2, (CH2)pZ is H or C1-C4 alkyl,R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted of unsubstituted when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition, Radiolabels can be incorporated into the structure through a variety of prosthetic, groups attached at the X amino acid side chain via a carbon or hetero atom linkage.