New approach to fight hormone dependent cancers using covalent inhibition of AKR1C3

Background

Aldo-keto reductase family 1 member C3 (AKR1C3) is a key enzyme involved in the metabolism of steroid hormones and prostaglandins, playing a central role in the progression of hormone-dependent cancers such as prostate, breast, and endometrial cancers, as well as in certain inflammatory diseases. Given its pivotal function in these pathologies, AKR1C3 has emerged as an attractive therapeutic target. The development of selective inhibitors for AKR1C3 is highly sought after, as such agents could provide new treatment options for patients with hormone-driven malignancies and inflammatory conditions. However, the high degree of sequence and structural similarity among the 14 human AKR family members presents a significant challenge for achieving isoform-specific inhibition, which is crucial to avoid unwanted side effects and maximize therapeutic efficacy. Current approaches to AKR1C3 inhibition predominantly rely on reversible inhibitors, which often lack sufficient selectivity due to the conserved nature of the active sites across AKR isoforms. This lack of selectivity can result in off-target inhibition of other AKR enzymes, such as AKR1D1, leading to serious adverse effects including hepatotoxicity, as observed in clinical candidates like BAY1128688. Furthermore, the inability to distinguish AKR1C3 from closely related isoforms limits the therapeutic window and complicates the clinical development of these inhibitors. Existing chemistries for covalent modification, such as those targeting catalytic residues, also struggle with selectivity, as these residues are often conserved. As a result, there is a pressing need for strategies that can achieve potent and highly selective inhibition of AKR1C3 without compromising safety or affecting related enzymes.

Technology description

This technology centers on the development of highly selective covalent inhibitors for the enzyme aldo-keto reductase family 1 member C3 (AKR1C3), which plays a pivotal role in hormone-dependent cancers and inflammatory diseases. Utilizing sulfonyl-triazole exchange (SuTEx) chemistry, the approach enables the covalent modification of a unique, non-catalytic tyrosine residue (Y24) found only in AKR1C3. The lead compound demonstrates exceptional potency and selectivity by irreversibly binding to this residue, thereby inactivating the enzyme. The platform also includes a tailored probe for mechanistic studies and detection. Comprehensive structure-activity relationship studies and chemoproteomic profiling have guided the optimization of these compounds, ensuring minimal off-target effects across the highly homologous AKR family and the broader proteome. The technology is supported by detailed protocols for chemical synthesis, cell-based assays, and advanced proteomic analyses, making it accessible for both therapeutic and research applications. What differentiates this technology is its unprecedented selectivity and tunability, overcoming a major challenge in targeting AKR1C3 due to the high sequence similarity among AKR isoforms. Traditional reversible inhibitors often lack specificity, resulting in off-target toxicity, such as hepatotoxicity from AKR1D1 inhibition. In contrast, this SuTEx chemistry platform allows for precise tuning of both the leaving and adduct groups, enabling the rational design of inhibitors that covalently target a non-conserved site unique to AKR1C3. This selectivity was rigorously validated through biochemical, cell-based, and chemoproteomic assays, with the lead compound showing over 1700-fold selectivity against closely related isoforms. The ability to irreversibly inactivate AKR1C3 with minimal impact on other proteins not only enhances therapeutic safety but also expands the utility of SuTEx chemistry for mapping protein-ligand interactions and discovering new druggable sites within challenging protein families.

Benefits

Highly selective covalent inhibition of AKR1C3, minimizing off-target effects and toxicity

Irreversible modification of a unique non-catalytic tyrosine ensures isoform specificity

Potent inhibition with low nanomolar IC50 values, enhancing therapeutic efficacy

Tunable SuTEx chemistry allows optimization of reactivity and selectivity through chemical modifications

Broad applicability for chemoproteomic profiling and discovery of novel protein functional sites

Reduced risk of hepatotoxicity and other side effects compared to reversible inhibitors

Validated methods for synthesis, biochemical assays, and proteomic analysis facilitate reproducibility and further development

Potential therapeutic use in hormone-dependent cancers and inflammatory diseases

Commercial applications

Hormone-dependent cancer therapeutics

Endometriosis treatment development

Inflammatory disease drug discovery

Proteome-wide chemoproteomic profiling

Selective covalent probe design

Additional Information

This describes novel compositions and methods for the covalent inactivation of aldo-keto reductase family 1 member C3 (AKR1C3). Utilizing sulfonyl-triazole exchange (SuTEx) chemistry, these compounds selectively modify a unique non-catalytic tyrosine residue on AKR1C3. This approach achieves high potency and exceptional isoform selectivity, minimizing off-target effects. The lead compound targets AKR1C3, an enzyme involved in hormone-dependent cancers and inflammatory diseases.