Treatment of breast cancer with selective androgen receptor modulators and cyclin-dependent kinase 4/6 inhibitors

1 . A method for treating a subject suffering from breast cancer comprising administering to said subject a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor, wherein said SARM compound is represented by a structure of formula I:

wherein

X is a bond, O, CH 2 , NH, S, Se, PR, NO, or NR;

G is O or S;

T is OH, OR, —NHCOCH 3 , or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;

R 3 is H, F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, or SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

n is an integer of 1-4; and

m is an integer of 1-3, or

an optical isomer, a racemic mixture, a pharmaceutically acceptable salt, a pharmaceutical product, a hydrate, an N-oxide, or a crystal thereof.

2 . The method according to claim 1 , wherein said breast cancer is an AR-positive breast cancer, ER-positive breast cancer, triple negative breast cancer, HER2-positive breast cancer, advanced breast cancer, refractory breast cancer, metastatic breast cancer, or breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, abemaciclib (Vorzenio), lerociclib), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), alpelisib (Piqray) (an inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose polymerase (PARP)), bevacizumab (Avastin), and/or fulvestrant treatments.

3 . The method according to claim 1 , wherein said breast cancer is AR-positive metastatic breast cancer or AR-positive refractory breast cancer.

4 . The method according to claim 1 , wherein said breast cancer has failed treatment with a selective estrogen receptor modulator (SERM).

5 . The method according to claim 4 , wherein said SERM is tamoxifen, toremifene, or raloxifene.

6 . The method according to claim 1 , wherein said breast cancer has failed treatment with a cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor.

7 . The method according to claim 6 , wherein said subject is resistant or non-responsive to the CDK 4/6 inhibitor.

8 . The method according to claim 6 , wherein said CDK 4/6 inhibitor is palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, lerociclib, or abemaciclib (Vorzenio).

9 . The method according to claim 6 , wherein said CDK 4/6 inhibitor is palbociclib (Ibrance).

10 . The method according to claim 1 , wherein said method re-sensitizes said breast cancer to treatment with CDK 4/6 inhibitors.

11 . The method according to claim 1 , wherein said method overcomes estrogen endocrine resistance.

12 . The method according to claim 11 , wherein said method overcomes resistance to estrogen endocrine and CDK 4/6 inhibitor co-therapy.

13 . The method according to claim 12 , wherein said estrogen endocrine therapy includes at least one of tamoxifen, toremifene, raloxifene, exemestane, letrozole, anastrozole, and fulvestrant.

14 . The method according to claim 12 , wherein said CDK 4/6 inhibitor is at least one of palbociclib (Ibrance), ribociclib (Kisqali), trilaciclib, lerociclib, and abemaciclib (Vorzenio).

15 . The method according to claim 1 , wherein said breast cancer has failed treatment with an mTOR inhibitor.

16 . The method according to claim 15 , wherein said mTOR inhibitor is everolimus, sirolimus, temsirolimus, or ridafarolimus.

17 . The method according to claim 2 , wherein said ER-positive breast cancer is AR-positive and ER-positive breast cancer, or AR-negative and ER-positive breast cancer.

18 . The method according to claim 2 , wherein said AR-positive breast cancer is ER-negative; ER-negative, PR-negative, and HER2-negative; ER-negative, PR-negative, and HER2-positive; ER-negative, PR-positive, and HER2-negative; ER-negative, PR-positive, and HER2-positive; ER-positive, PR-negative, and HER2-negative; ER-positive, PR-positive, and HER2-negative; ER-positive, PR-negative, and HER2-positive; or ER-positive, PR-positive, and HER2-positive.

19 . The method according to claim 1 , wherein said method further prolongs the survival of the subject suffering from breast cancer or prolongs the progression-free survival of the subject suffering from breast cancer.

20 . The method according to claim 1 , wherein said selective androgen receptor modulator is administered intravenously, intraarterially, intramuscularly, subcutaneously, orally, or topically.

21 . The method according to claim 1 , wherein said selective androgen receptor modulator is dosed from 1 mg to 50 mg per day.

22 . The method according to claim 1 , wherein said selective androgen receptor modulator is dosed at 9 mg per day.

23 . The method according to claim 1 , wherein said selective androgen receptor modulator is dosed at 18 mg per day.

24 . The method according to claim 1 , wherein said SARM compound is represented by a structure of formula II:

wherein

X is a bond, O, CH 2 , NH, Se, PR, or NR;

G is O or S;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is I, CF 3 , Br, Cl, or Sn(R) 3 ;

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

R is a C 1 -C 4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a C 1 -C 4 haloalkyl, halogen, or haloalkenyl; and

R 1 is CH 3 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .

25 . The method according to claim 1 , wherein said SARM compound is represented by a structure of formula VIII, IX, X, XI, XII, XIII, or XIV:

26 . The method according to claim 1 , wherein said SARM compound is represented by a structure of Formula IX,