Multivalent Peptoid Scaffolds for Androgen Receptor Modulation

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Solution Overview

Problem

Current therapeutic options for prostate cancer, particularly those targeting androgen receptor (AR) activity, are limited in effectively addressing advanced prostate cancer and often lead to drug resistance due to mutations within the AR-ligand binding domain.

Innovation Solution

Development of multivalent peptoid scaffolds as competitive or non-competitive AR modulators that can be administered to mammals to prevent, treat, or ameliorate medical conditions associated with aberrant AR activity, including prostate cancer, by utilizing synthetic oligomers with specific chemical structures and linkages to enhance binding avidity and stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If competitive DHT antagonists such as bicalutamide are used to block AR signaling, then tumor growth is suppressed initially, but drug resistance develops due to mutations within the AR-LBD

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoiddrug resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent inverts the conventional approach by using multivalent peptoid scaffolds that bind to the AR-LBD in a non-competitive manner, occupying the ligand-binding pocket with multiple binding sites rather than using single-site competitive antagonists. This multivalent binding strategy prevents the conformational changes that lead to drug resistance mutations while maintaining therapeutic effectiveness.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention employs composite multivalent peptoid structures composed of multiple binding units linked together. These composite scaffolds combine multiple weak binding interactions into a single high-avidity interaction with the AR-LBD, creating a more stable and resistant-to-mutation therapeutic agent compared to single-site competitive antagonists.

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If multivalent peptoid scaffolds are used to enhance binding avidity, then binding stability is improved, but molecular complexity increases

Engineering Contradiction:

Improvebinding stabilityVSAvoidmolecular complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The multivalent peptoid scaffolds are constructed by segmenting the binding function into multiple identical or similar binding units that are repetitively linked together. This modular segmentation allows for enhanced binding avidity through multiple interaction sites while maintaining a relatively simple and repetitive molecular architecture that facilitates synthesis and characterization.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20240165245A1Multivalent peptoid oligomers, pharmaceutical compositions and methods of using same

Publication Date: 2024.05.23 NEW YORK UNIV

AI summary

Novel peptoid oligomers are disclosed that have a formula represented by the following formula Ia or Ib:The peptoid oligomers are prepared as modulators of androgen receptor (AR), and may be prepared as pharmaceutical compositions and used for the prevention or treatment of a variety of conditions in mammals, including humans, associated with unwanted or aberrant AR activity. The present peptoid oligomers are particularly valuable for the treatment of subjects with cancer.