Allosteric modulators of androgen receptor coactivator recruitment for crpc therapy

A method of modulating androgen receptor-mediated activity, comprising:

• contacting androgen receptor with an effective amount of a compound, wherein the compound is a hydrobenzo-oxazepine, a thiadiazol-5-piperidine carboxamide, a fluorophenyl-methyl-indole, a phenyl-methyl-indole, a heteroaliphatic- or heteroaryl-substituted methyl-indole, or any combination thereof, thereby inhibiting androgen receptor-coactivator (AR-CoA) protein-protein interaction (PPI) complexes, inhibiting prostate specific antigen (PSA) expression in prostate epithelial cells and/or prostate cancer cells, inhibiting PSA secretion by prostate epithelial cells and/or prostate cancer cells, inhibiting AR-mediated PSA promoter-driven transcription in prostate cancer cells, inhibiting androgen receptor splice variant 7 (AR-V7)-mediated PSA promoter driven transcription in prostate cancer cells, inhibiting ubiquitin conjugating enzyme E2 C (UBE2C) promoter-driven transcription in prostate cancer cells, inhibiting growth of prostate cancer cells, or any combination thereof,
• wherein the compound has a structure according to any one of formulas I-III:
• wherein
• R1 is aryl or heteroaryl;
• R2 is a heterocycle;
• R3 is H;
• X1 is S, O, or N;
• R4 is —X2—Ra or halo, where X2 is CH2, S, or O, and Ra is aryl or heteroaryl;
• R5 is aliphatic or a heterocycle;
• R6 is —CH2N(H)Y(CH2)m—Rb, H, halo, or alkyl, where Y is C(O) or S(O)2, Rb is a heterocycle or —N(H)Y(CH2)mCH3, and each m independently is 0, 1, 2, or 3;
• R7 is aryl, heteroaryl, H, or alkyl:
• R8 is alkyl, aryl, a heterocycle, or H;
• and
• R9 is H, alkyl, or —CH2N(H)Y(CH2)m—R,
• wherein at least one of R6 and R9 is not H,
• at least one of R7 and R1 is not H, and
• one of R6-R9 is —CH3.