Selective Androgen Receptor Covalent Antagonists for CRPC Resistance
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Solution Overview
Problem
Current treatments for advanced prostate cancer, particularly castration-resistant prostate cancer (CRPC), are limited by the re-activation of the androgen receptor (AR) through alternate mechanisms, including AR splice variants and mutations, which are not effectively inhibited by existing AR antagonists, leading to treatment resistance and disease progression.
Innovation Solution
Development of selective androgen receptor covalent antagonists (SARCAs) that irreversibly bind to the N-terminal domain (NTD) of the AR, including the AF-1 region, to inhibit both AR full-length and splice variant-dependent proliferation, offering dual degradation and inhibitory functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional AR antagonists (enzalutamide, abiraterone, bicalutamide) are used to treat CRPC, then initial response is achieved, but treatment resistance develops due to AR re-activation through splice variants and mutations
Solution Approach 1:
The invention segments the AR protein into two distinct binding targets: the N-terminal domain (NTD) and the ligand-binding domain (LBD). SARCAs simultaneously target both domains, with covalent binding to NTD providing irreversible inhibition of AR splice variants (which lack LBD), while LBD binding provides reversible antagonism. This segmented targeting strategy overcomes resistance mechanisms that affect only one domain.
Solution Approach 2:
The invention performs preliminary action by introducing a covalent warhead that irreversibly modifies the NTD of AR before the cancer can develop resistance through splice variants or mutations. This preliminary covalent binding prevents the receptor from being re-activated through alternate mechanisms, establishing long-term inhibition that precedes and prevents resistance development.
2Adaptability or versatility
If AR antagonists act through the LBD, then they can inhibit wild-type AR, but they fail to inhibit AR splice variants that lack the LBD
Solution Approach 1:
The SARCA molecule performs multiple functions: it acts as a covalent irreversible antagonist at the NTD (effective against all AR forms including splice variants) and as a reversible competitive antagonist at the LBD (effective against wild-type AR). This multi-functionality allows a single compound to inhibit both full-length AR and AR splice variants, achieving universal activity across different AR forms.
Solution Approach 2:
The NTD binding site serves as an intermediary target that is present in all AR forms (wild-type and splice variants). By introducing a covalent warhead that targets this intermediary NTD domain, the invention creates a common point of inhibition that works regardless of whether the LBD is present or mutated, thereby bridging the gap between wild-type and variant AR inhibition.
3Duration of action of stationary object
If reversible AR antagonists are used, then they can be displaced by increased agonist levels, but covalent irreversible binding provides sustained inhibition
Solution Approach 1:
The invention changes the binding parameter from reversible (equilibrium-based) to irreversible (covalent). By incorporating a covalent warhead that forms permanent chemical bonds with the NTD cysteine residues, the duration of action is extended from transient to permanent at the molecular level. This parameter change from reversible to irreversible binding fundamentally alters the pharmacokinetic and pharmacodynamic profile of the AR antagonist.
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
SARCAs provide potent and irreversible inhibition of AR, effectively targeting treatment-resistant CRPC and other AR-dependent diseases, including prostate cancer, breast cancer, androgenic alopecia, and uterine fibroids, by degrading AR and preventing re-activation, thus overcoming resistance mechanisms and improving treatment outcomes.
Implementation Method 1
selective androgen receptor covalent antagonists (SARCAs) that irreversibly bind to the N-terminal domain (NTD) of the AR
Implementation Method 2
offering dual degradation and inhibitory functions
Data Source
AI summary
This invention relates to selective androgen receptor covalent antagonists, synthetic intermediates and by-products, and related compounds, and compositions comprising the same, and uses thereof in treating androgen receptor dependent diseases and conditions such as hyperproliferations of the prostate including pre-malignancies and benign prostatic hyperplasia, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR.