Androgen receptor (AR) is a member of the nuclear hormone receptor family activated by androgens, such as dihydrotestosterone (DHT). AR is a prime therapeutic target for treating prostate cancer. Several compounds have been developed as chemotherapy for prostate cancer. However, these compounds bind AR with affinities comparable to or less than the endogenous hormone and over time patients develop resistance to these drugs. Higher affinity and/or slower off-rate ligands (e.g. covalent ligands) are needed to provide more effective therapies.
Androgen receptor competitive antagonists (antiandrogens) are drugs used to treat hormonal-based syndromes and prostate cancer. Current drugs for prostate cancer include flutamide, bicalutamide, nilutamide, enzalutamide and ARN-509. Each of these inhibitors binds to the hormone-binding pocket (HBP) of the androgen receptor. This is the same site that the natural physiological steroids testosterone (TES) and dihydrotestosterone (DHT) situate to produce an active conformation of the receptor that changes the cell's transcription program and cell fate. The drugs work by competing with the natural hormones for binding to the pocket and, as a result, lessening activation of the receptor. Of all these ligands, the steroids DHT and testosterone bind tightest to the receptor. Tighter binding and/or slower off-rate drugs are desirable, along with the additional characteristic that they encourage degradation of the receptor by components resident in cells and/or prevent formation of AR variants resistant to chemotherapy.
Disclosed herein are solutions to these and other problems in the art.
USPTO Backgrounds
USPTO Backgrounds