Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide
The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
1. A compound having the chemical structure:
ULM-L-PTM,
or a pharmaceutically acceptable salt thereof,
wherein:
(a) the ULM is:
wherein:
W is CH 2 or C═O;
A is H;
represents a bond that may be stereospecific or non-stereospecific;
n is 1; and
R is a bond to the chemical linking moiety or NHR′ covalently joined to the chemical linking moiety;
R′ is alkyl;
(b) the L is a chemical linking moiety connecting the ULM and the PTM which comprises (1) a chemical structural unit represented by the formula:
—(CH 2 )m-O(CH 2 )n-O(CH 2 )o-O(CH 2 )p-O(CH 2 )q-O(CH 2 )r-O—, —NH—(CH 2 )m-O(CH 2 )n-O(CH 2 )o-O(CH 2 )p-O(CH 2 )q-O(CH 2 )r-O—;
wherein:
each m, o, p, q, and r of the chemical linking moiety are independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero, there is no N—O or O—O bond;
n of the chemical linking moiety is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
(2) a polyethylenoxy group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ethylene glycol units; and
(c) the PTM is PTM-I-1, PTM-IVa-1, or PTM-IVb-1:
wherein:
W PTM and X PTM are independently C or N;
Y PTM and Z PTM are CH;
X PTM1 is NH or O;
X PTM2 is absent;
R PTM is methyl or methoxy;
R PTM5 is methyl; and
indicates a covalent linkage to the chemical linking moiety.
2. The compound according to claim 1 , wherein L is:
3. The compound according to claim 1 , wherein the chemical linking moiety (L) is a polyethylenoxy group comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ethylene glycol units.
4. A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5 , wherein the composition further comprises at least one additional bioactive agent.
7. The pharmaceutical composition of claim 6 , wherein the additional bioactive agent is an anti-cancer agent.
8. A method of treating a disease or disorder, associated with EZH2 accumulation and aggregation the method comprising administering a compound of claim 1 to a subject.
9. The method of claim 8 , wherein the disease or disorder is cancer.
10. The method of claim 8 , wherein the disease or disorder is breast cancer, prostate cancer, bladder cancer, uterine cancer, renal cancer, melanoma, and/or lymphoma.
11. A pharmaceutical composition comprising a compound of claim 4 , and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11 , wherein the composition further comprises at least one additional bioactive agent.
13. The pharmaceutical composition of claim 12 , wherein the additional bioactive agent is an anti-cancer agent.
14. A method of treating a disease or disorder, associated with EZH2 accumulation and aggregation the method comprising administering a compound of claim 4 to a subject.
15. The method of claim 14 , wherein the disease or disorder is cancer.
16. The method of claim 14 , wherein the disease or disorder is breast cancer, prostate cancer, bladder cancer, uterine cancer, renal cancer, melanoma, and/or lymphoma.