Electrophilic androgen receptor (AR) antagonists for AR downregulation and ferroptosis induction in cancer cells
Inventors
Assignees
Publication Number
US-12133846-B2
Publication Date
2024-11-05
Expiration Date
2040-10-15
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Abstract
Isothiocyanate (ITC)-androgen receptor (AR) inhibitor conjugates for apoptosis induction in cancer cells are described. The conjugates can have electrophilicity blocked with an agent such as N-acetyl cysteine. When administered in combination with a glutathione (GSH)-depleting agent, the conjugates result in ferroptosis of cancer cells.
Core Innovation
The invention provides isothiocyanate (ITC)-androgen receptor (AR) inhibitor conjugates as a new class of hybrid drugs for inducing apoptosis and ferroptosis in cancer cells. By incorporating an ITC moiety into the chemical scaffold of an AR inhibitor, these hybrid drugs possess both AR antagonist activity and the ability to downregulate AR/AR splice variants. The hybrid drugs can have their electrophilicity transiently reduced or blocked with agents like N-acetyl cysteine (NAC), forming NAC conjugates that gradually release the active ITC in physiological conditions.
The invention addresses the problem of treatment resistance in prostate cancer, specifically castration-resistant prostate cancer (CRPC), which often exhibits resistance to classical androgen-deprivation therapies, including AR inhibitors like enzalutamide. CRPC cells can continue to depend on AR signaling through overexpression, mutations, or splice variants that conventional therapies cannot effectively target, highlighting the need for more effective drugs capable of antagonizing AR signaling and overcoming resistance.
A distinctive aspect of the disclosed ITC-AR inhibitor conjugates is their synergistic effect in combination with glutathione (GSH)-depleting agents such as buthionine sulphoximine (BSO). The combination enables the induction of ferroptosis—a form of cell death distinct from apoptosis—particularly effective in apoptosis-resistant cancer cells. The invention also provides methods and compositions for treating AR-positive cancers, including CRPC, by deploying these ITC-AR inhibitor conjugates and combination regimens to downregulate AR and induce cancer cell death through ferroptosis.
Claims Coverage
The patent contains several independent claims covering the novel AR inhibitor compounds, compositions, and methods for inducing cancer cell death, including combination therapies with GSH-depleting agents.
Androgen receptor (AR) inhibitors of specific formulae
The invention claims AR inhibitors of Formula II, III, IV, V, or their salts, comprising molecular structures that incorporate an isothiocyanate (ITC) group into an AR inhibitor scaffold. These compounds are characterized by their chemical structure as outlined in the claims and are designed to provide AR binding affinity, AR antagonism, and the capacity to induce cancer cell death.
Compositions including the AR inhibitor and a carrier
Compositions are claimed that include the AR inhibitor of the defined formulae along with a carrier. These may be pharmaceutical or non-pharmaceutical carriers, supporting administration via various routes as described in the patent.
Pharmaceutical compositions with a pharmaceutically acceptable carrier
Pharmaceutical compositions containing the AR inhibitor or its salt in combination with a pharmaceutically acceptable carrier are specified, enabling therapeutic use of the active compounds.
Method of inducing cancer cell death by administering the AR inhibitor
The patent claims a method for inducing cancer cell death by administering the AR inhibitor to subjects in need thereof, resulting in the destruction of cancer cells. This includes application to various cancer types as detailed.
Method of combination treatment with a glutathione (GSH)-depleting agent
The claims cover a method where the AR inhibitor is administered in combination with a GSH-depleting agent, such as buthionine sulphoximine (BSO) or imidazole ketone erastin, to a subject. The combination enables synergistic effects, particularly induction of ferroptosis.
Cancer treatment, including prostate cancer and resistant forms
Methods are claimed for treating subjects with prostate cancer, including castration-resistant prostate cancer, and cancers resistant to apoptosis-inducing anti-cancer agents, by using the AR inhibitor alone or in combination with a GSH-depleting agent.
In summary, the claims cover novel ITC-modified AR inhibitors, compositions containing these inhibitors, pharmaceutical formulations, and therapeutic methods—including combination therapies targeting apoptosis-resistant and castration-resistant prostate cancer—by leveraging AR downregulation and induction of ferroptosis.
Stated Advantages
The hybrid drugs can induce cancer cell death through ferroptosis, providing a treatment option against apoptosis-resistant cancer cells.
Combination with GSH-depleting agents creates synergistic anti-cancer effects, enhancing the potency and specificity towards malignant cells.
The NAC conjugate form offers improved water solubility and selectivity, increasing tolerability in noncancerous cells and acting as a prodrug that avoids acute electrophilic attack.
Downregulation of full-length AR and AR splice variants addresses resistance mechanisms in castration-resistant prostate cancer not targeted by classical AR inhibitors.
The hybrid drug design allows co-localization of AR inhibitor and ITC pharmacophores, generating new anti-cancer properties not present in existing therapies like enzalutamide.
Documented Applications
Treatment of AR-positive cancers, including prostate cancer and castration-resistant prostate cancer (CRPC).
Treatment of prostate cancers that have become resistant to apoptosis-inducing anti-cancer agents.
Induction of ferroptosis in cancer cells using ITC-AR inhibitor conjugates in combination with GSH-depleting agents.
Use in cancer cell death methods in vitro and within a subject, as well as inclusion in kits and compositions for clinical or research use.
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