FN14 antagonists and therapeutic uses thereof
View Patent ↗The present disclosure is directed to methods of using fibroblast growth factor-inducible 14 (Fn14) antagonists to modulate activity at a TNF-like weak inducer of apoptosis (TWEAK) binding site on a cysteine-rich domain (CRD) of Fn14. The present disclosure also provides pharmaceutical compositions comprising synergistic combinations Fn14 antagonists and chemotherapeutic agents.
1. A method of inhibiting the TWEAK-Fn14 pathway in a cell, the method comprising administering to the cell an Fn14 antagonist comprising a compound of Formula (II):
or a salt thereof, wherein
R 1 is —H, —OH, —NH 2 , —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), —SO 2 NH 2 ,
and a vehicle, excipient, and/or carrier.
2. The method of claim 1 , wherein R 1 of the compound or salt is —H, —OH, halo, —C 1-6 alkyl, or —O—C 1-6 alkyl.
3. The method of claim 2 , wherein the compound is:
4. A pharmaceutical composition comprising a synergistic combination of an Fn14 antagonist comprising a compound of Formula (II):
or a salt thereof, wherein
R 1 is —H, —OH, —NH 2 , —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), —SO 2 NH 2 ;
and a chemotherapeutic alkylating agent.
5. The pharmaceutical composition of claim 4 , wherein the chemotherapeutic alkylating agent is selected from the group consisting of mechtorethamine, cyclophosphamide, chlorambucil, melphalane, trofosfamide, ifosfamide, carmustine, lomustine, darcarbazine, temozolomide (TMZ), and mitomycine C.
6. A new method of treating a cancer selected from the group consisting of a brain tumor, glioblastoma, breast cancer, esophageal cancer, lung cancer, and melanoma, the method comprising administering to a subject in need thereof an effective amount of an Fn14 antagonist comprising a compound of Formula (II):
or a salt thereof, wherein
R 1 is —H, —OH, —NH 2 , —N(alkyl)(alkyl), hydrocarbyl, —O-hydrocarbyl, aryl, —O-aryl, aralkyl, —O-aralkyl, heteroaryl, —O-heteroaryl, heterocyclyl, —O-heterocyclyl, halo, —OCF 3 , —C(O)O(alkyl), —OC(O)(alkyl), —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —OC(O)O(alkyl), —OC(O)NH 2 , —OC(O)NH(alkyl), —OC(O)N(alkyl)(alkyl), —CHNH, —CHN(alkyl), —SO 2 NH 2 ;
and a vehicle, excipient, and/or carrier.
7. The method of claim 6 , wherein the compound inhibits the TWEAK-Fn14 pathway in the subject.
8. The method of claim 6 , wherein R 1 of the compound or salt is —H, —OH, halo, —C 1-6 alkyl.
9. The method of claim 8 , wherein the compound is: