Androgen receptor down-regulating agents and uses thereof
The present disclosure provides the design and synthesis of novel steroidal compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant. The compounds are potential agents for the treatment of all forms of prostate cancer and other diseases that depend on functional AR.
1. A method of inhibiting androgen receptor (AR) activity in a cell, the method comprising a step of:
down-regulating androgen receptor (AR) level in a cell, wherein the step of down-regulating comprises administering a composition that delivers to the cell a steroidal compound and wherein the compound is characterized by an ability to inhibit growth of CWR22Rv1 cells with a GI50 below about 15 μM.
2. The method of claim 1 , wherein the compound is not an androgen synthesis inhibitor more potent than a reference compound selected from abiraterone acetate, TAK-700, or galeterone.
3. The method of claim 1 , wherein the compound is not an AR antagonist more potent than a reference compound selected from abiraterone acetate, TAK-700, or galeterone.
4. The method of claim 1 , wherein the compound is characterized in that exposure of a cell comprising AR to the compound results in down-regulation of AR, inhibition of AR mediated transcription and inhibition of cell growth.
5. The method of claim 4 , wherein the down-regulation of AR and inhibition of AR mediated transcription occur before the cell growth inhibition.
6. The method of claim 1 , wherein the compound is characterized by an ability to inhibit CYP17 with an IC50 below 1 μM.
7. The method of claim 1 , wherein the cell has both full-length and splice variant androgen receptor.
8. The method of claim 7 , wherein the splice variant androgen receptor is lacking the ligand binding domain.
9. The method of claim 7 , wherein the splice variant androgen receptor is AR-V7.
10. The method of claim 1 , wherein the cell is not responsive to AR anti-androgens or androgen deprivation therapy.
11. A method of claim 1 , wherein the cell is resistant to abiraterone acetate.
12. A method of claim 1 , wherein the cell is resistant to enzalutamide.
13. The method of claim 1 , wherein the cell is an androgen-related disease cell.