DOT1L degraders and uses thereof
Provided herein are bifunctional compounds with a moiety or domain that is a binder of the ubiquitin receptor RPN13 and another moiety or domain that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one domain of the bifunctional compound is a binder of the ubiquitin receptor RPN13 and another domain of the compound is a binder of the target protein DOT1L in a subject.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
R 8 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R 9 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R 10 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R 11 is halogen, optionally substituted acyl, or optionally substituted alkyl;
each instance of R 12 is independently hydrogen, optionally substituted acyl, or an oxygen protecting group;
L is
and
l R indicates the point of attachment to D, and l A indicates the point of attachment to the moiety of formula
X is —CH 2 — or —O—;
ring B is an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-14 membered heteroaryl group;
n1 is 1, 2, 3, 4, 5, or 6;
n2 is 1, 2, 3, 4, 5, or 6;
n3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
g is 1, 2, 3, 4, 5, or 6; and
g1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
D is of the formula IA or IB:
wherein:
for each set of two moieties A bound to the same carbon atom, one A is hydrogen, and the other A is one of:
(i) phenyl, optionally substituted with 1-5 substituents selected from the group consisting of —R 1 , —OR 1 , —NR 1 R 2 , —S(O) q R 1 , —SO 2 R 1 R 2 , —NR 1 SO 2 R 2 , —C(O)R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O) R 2 , —NR 1 C(O)OR 2 , —CHF 2 , —CH 2 F, —CF 3 , and —OCF 3 ;
(ii) naphthyl, optionally substituted with 1-5 substituents selected from the group consisting of —R 1 , —OR 1 , —NR 1 R 2 , —S(O) q R 1 , —SO 2 R 1 R 2 , —NR 1 SO 2 R 2 , —C(O) R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O) R 2 , —NR 1 C(O)OR 2 , —CHF 2 , —CH 2 F, —CF 3 , and —OCF 3 ;
(iii) a 5- or 6-membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of —R 1 , —OR 1 , —NR 1 R 2 , —S(O) q R 1 , —SO 2 R 1 R 2 , —NR 1 SO 2 R 2 , —C(O) R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O) R 2 , —NR 1 C(O)OR 2 , —CHF 2 , —CH 2 F, —CF 3 , and —OCF 3 ; and
(iv) an 8- to 10-membered bicyclic heteroaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S, and having a first ring fused to a second ring through 3 to 4 carbon atoms, wherein the bicyclic heteroaryl group is optionally substituted with 1-3 substituents selected from the group consisting of —R 1 , —OR 1 , —NR 1 R 2 , —S(O) q R 1 , —SO 2 R 1 R 2 , —NR 1 SO 2 R 2 , —C(O) R 1 , —C(O)OR 1 , —C(O)NR 1 R 2 , —NR 1 C(O) R 2 , —NR 1 C(O)OR 2 , —CHF 2 , —CH 2 F, —CF 3 , and —OCF 3 ;
Y is ═O, ═S, ═NR 1 , or ═CR 1 R 2 , R 1 and R 2 are each independently selected from the group consisting of hydrogen, nitro, hydroxyl, —COOH, —NH 2 , halogen, cyano, and C 1 -C 14 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 14 alkyl, C 1 -C 14 haloalkyl, C 1 -C 14 alkoxy, nitro, hydroxyl, —COOH, —NH 2 , C 1 -C 14 alkylamino, C 1 -C 14 dialkylamino, halogen, and cyano;
R 7 is hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group;
Z is selected from the group consisting of hydrogen, optionally substituted C 1 -C 14 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkyl-aryl, and —(CH 2 ) p —K;
K is a 5- or 6-membered monocyclic heterocyclic or heteroaryl group containing 1-4 heteroatoms selected from the group consisting of O, N, and S, or an 8- to 10-membered bicyclic heteroaryl group containing 1-4 heteroatoms selected from the group consisting of O, N, and S;
p is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein D is of the formula:
3. The compound of claim 2 , wherein:
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is phenyl optionally substituted with R 1 ;
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is phenyl substituted with halogen;
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is phenyl substituted with two instances of halogen;
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is phenyl substituted with at least one Cl;
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is naphthyl optionally substituted with R 1 ;
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is a 5- or 6-membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with R 1 ; or
for each set of two moieties A bound to the same carbon atom, one A is hydrogen and the other A is an 8- to 10-membered bicyclic heteroaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S, and having a first ring fused to a second ring through 3 to 4 carbon atoms, wherein the bicyclic heteroaryl group is optionally substituted with R 1 .
4. The compound of claim 2 , wherein:
Y is ═O;
Z is (C 1-3 alkyl) phenyl, (C 1-3 haloalkyl) phenyl, or phenyl; or
R 7 is hydrogen.
5. The compound of claim 4 , wherein Z is benzyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein D is of formula:
7. The compound of claim 1 , wherein the compound is of
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
8. The compound of claim 7 , wherein R 11 is optionally substituted C 1-6 alkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L is
10. The compound of claim 1 , wherein L is of the formula:
11. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate, thereof.
12. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate, thereof, wherein X is CH 2 or O; and
g1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
13. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.
15. A method of inducing the degradation of DOTIL in a subject, comprising:
administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
16. A method of inducing degradation of DOTIL in a cell, tissue, or biological sample comprising:
contacting the cell, tissue, or biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
17. The compound of claim 7 , wherein the compound is of formula:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.