Bi-functional compounds and methods for targeted ubiquitination of androgen receptor
The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.
1. A compound having a chemical structure ARB-L-E3LB, wherein ARB is an AR binding moiety that does not bind to a ligand binding domain, E3LB is an E3 ligase binding moiety, and L is a linker coupling the AR binding moiety to the E3 ligase binding moiety; wherein the AR binding moiety is:
wherein each R 1 is independently selected from H, CH 3 , and halo; and
wherein the E3 ligase binding moiety is a structure selected from:
wherein in each moiety:
R 8 is H, a straight chain or branched C 1-8 alkyl, C 3-6 cycloalkyl, halo, CFH 2 , CF 2 H, or CF 3 ;
R 9 is H, halo, 4-methylthiazol-5-yl, or oxazol-5-yl;
R 10 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted branched alkyl, optionally substituted heterocycloalkyl, (CH 2 ) v COR 14 , CH 2 CHR 15 COR 16 , CH 2 R 17 and optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, where v=1 to 3;
R 14 and R 16 are independently selected from OH, and NR 18 R 19 ;
R 15 is —NR 18 R 19 ;
R 17 is optionally substituted aryl or optionally substituted heterocycloalkyl, wherein the optional substituents are selected from alkyl and halogen;
R 18 is hydrogen or optionally substituted alkyl;
R 19 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, —CH 2 (OCH 2 CH 2 O) w CH 3 , or a polyamine chain, where w=1 to 8;
R 11 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkylalkyl, wherein the optional substituents are selected from alkyl, halogen, and OH.
2. The compound of claim 1 , wherein the AR binding moiety binds to one more of AR splice variants V1 to V15.
3. The compound of claim 1 , wherein the E3 ligase binding moiety is the structure:
wherein:
R 8 is H, a straight chain or branched C 1-8 alkyl, C 3-6 cycloalkyl, halo, CFH 2 , CF 2 H, or CF 3 ;
R 9 is H, halo, 4-methylthiazol-5-yl, or oxazol-5-yl;
R 10 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-alkyl, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted branched alkyl, optionally substituted heterocycloalkyl, (CH 2 ) v COR 14 , CH 2 CHR 15 COR 16 , CH 2 R 17 and optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, where v=1 to 3;
R 14 and R 16 are independently selected from OH, and NR 18 R 19 ;
R 15 is —NR 18 R 19 ;
R 17 is optionally substituted aryl or optionally substituted heterocycloalkyl, where the optional substituents are selected from alkyl and halogen;
R 18 is hydrogen or optionally substituted alkyl;
R 19 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, —CH 2 (OCH 2 CH 2 O) w CH 3 , or a polyamine chain, where w=1 to 8.
4. The compound of claim 1 , wherein the AR binding moiety is:
5. The compound of claim 1 , wherein the E3 ligase binding moiety is selected from the group consisting of:
6. The compound of claim 1 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 0-4;
wherein m is from 2-12;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein m is from 0-10;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 0-10.
7. The compound of claim 1 , wherein the AR binding moiety is:
and wherein the E3 ligase binding moiety is:
and
wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 2-4;
wherein m is from 0-12;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein m is from 0-10;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 0-10.
8. The compound of claim 1 , wherein the compound is effective in causing or promoting the degradation of the androgen receptor (AR) in a cell, or of causing or promoting apoptosis in a cell.
9. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, additive and/or excipient.
10. The compound of claim 1 , wherein the E3 ligase binding moiety is a structure selected from:
wherein in each moiety:
R 8 is selected from H, methyl, ethyl, isopropyl, tert-butyl, and cyclopropyl;
R 9 is 4-methylthiazol-5-yl, or oxazol-5-yl;
R 10 is selected from methyl, ethyl, isopropyl, tert-butyl and cyclopropyl;
R 11 is selected from methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, each optionally substituted with halogen or OH.
11. The compound according to claim 10 , wherein the AR binding moiety is
wherein each R 1 is independently selected from H and F.
12. The compound according to claim 11 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 0-12;
wherein m is from 2-4;
wherein m is from 0-12;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein m is from 0-10;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 0-10.
13. The compound according to claim 12 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein m is from 0-12;
wherein m is from 2-4;
wherein m is from 0-12;
wherein n is from 1-5; and
wherein n is from 1-5.
14. The compound according to claim 1 , wherein the linker (“L”) comprises a chemical structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl (optionally substituted with 0-6 R L1 and/or R L2 groups), and heteroaryl (optionally substituted with 0-6 R L1 and/or R L2 groups), wherein R L1 , R L2 , R L3 , and R L4 are each independently selected from the group consisting of H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocycloalkyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , SiC( 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 and NHSO 2 NH 2 , and wherein R L1 and R L2 each, independently may be linked to another A group to form a cycloalkyl and or heterocycloalkyl moiety that can be further substituted with 0-4 R L5 groups.
15. The compound according to claim 1 , wherein the compound is selected from the following:
16. The compound of claim 1 , wherein the linker (“L”) comprises a chemical structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, NR L3 , CONR L3 , CO, C 3-11 cycloalkyl, and heteroaryl (optionally substituted with 0-6 R L1 and/or R L2 groups), wherein R L1 , R L2 , and R L3 are each independently selected from the group consisting of H, halo, and C 1-8 alkyl.
17. The compound of claim 1 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 1-12.
18. The compound of claim 7 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 1-12.
19. The compound of claim 11 , wherein the linker group (“L”) is selected from:
wherein n is from 1-5;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 0-10;
wherein n is from 1-5;
wherein n is from 1-5;
wherein m is from 1-12;
wherein m is from 1-12; and
wherein m is from 1-12.