Aziridine Bisphenol Ethers Targeting AR N-Terminal Domain
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Solution Overview
Problem
Current treatments for prostate and ovarian cancers, particularly castration-resistant prostate cancer, are inadequate due to the limitations of existing androgen receptor (AR) inhibitors, which fail to effectively target the AR's N-terminal domain and do not address the issue of AR splice variants that lack the ligand-binding domain, leading to continued progression of androgen-independent cancer.
Innovation Solution
Development of bisphenol-related compounds that form covalent bonds with the AR receptor, specifically targeting the N-terminal domain, to modulate AR activity and inhibit its transcriptional activity, potentially used in combination with other therapeutic agents for enhanced therapeutic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional androgen receptor inhibitors are used, then AR activity is inhibited, but they fail to effectively target the N-terminal domain and AR splice variants, leading to treatment resistance
Solution Approach 1:
The compound is designed to simultaneously target multiple AR forms including full-length AR, AR splice variants lacking the LBD, and mutant AR forms. The N-terminal domain targeting capability provides universal inhibition across diverse AR configurations that conventional C-terminal inhibitors cannot address.
Solution Approach 2:
The invention shifts the inhibition site from the conventional C-terminal ligand-binding domain to the N-terminal transactivation domain. This local quality change enables the compound to bind to a different functional region of the AR, providing effective inhibition of AR splice variants that lack the C-terminal domain.
2Productivity
If androgen ablation therapy is used, then tumor burden is temporarily reduced, but castration-resistant disease develops with rising PSA levels
Solution Approach 1:
The compound performs preliminary action by targeting the N-terminal domain of AR before resistance develops. By inhibiting AR transactivation activity at its source in the N-terminal domain, the compound prevents the development of castration-resistant disease rather than merely delaying it, addressing the root cause of treatment failure.
Solution Approach 2:
The compound mimics the natural androgen binding to the N-terminal domain of the androgen receptor, but produces an inhibitory effect rather than activation. This copying mechanism allows the compound to exploit the natural AR structure and function while subverting its activity to achieve sustained tumor control.
3Reliability
If existing AR inhibitors are used, then some AR activity is blocked, but they do not address AR splice variants that lack the ligand-binding domain
Solution Approach 1:
The invention shifts the inhibition site from the conventional C-terminal ligand-binding domain to the N-terminal transactivation domain. This local quality change enables the compound to bind to a different functional region of the AR, providing effective inhibition of AR splice variants that lack the C-terminal domain.
Solution Approach 2:
The compound is designed to simultaneously target multiple AR forms including full-length AR, AR splice variants lacking the LBD, and mutant AR forms. The N-terminal domain targeting capability provides universal inhibition across diverse AR configurations that conventional C-terminal inhibitors cannot address.
Data Source
AI summary
Compounds having a structure of Formula I:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R, R1, R2, R3, R4, M1, M2, X, L1, L2, J1, J2, a1, a2, b1 and b2 are as defined herein, and wherein at least one of M2 or L2 is a moiety comprising an aziridine, acrylamide or sulfonate functional group, are provided. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.