The JNJ AR antagonist, JNJ-63576253, is a clinical molecule for prostate cancer that is active against both wild-type androgen receptor as well as the clinically relevant AR mutant, F877L. F887L is a devious resistance mechanism that transforms antagonists of AR into agonists. The parent compound from which 6253 is derived was found to be unacceptably hepatotoxic, which was suspected to be due to bioactivation of an electron rich phenyl ring. Replacing the phenyl ring with a pyridine, an often-effective strategy for mitigating bioactivation of aryl amines, led to the dramatically improved safety window observed for JNJ-63576253. JNJ-63576253/TRC-253 recently completed a Ph. I/II trial in mCRPC.