Inhibition of NGLY1 for the treatment of cancer
AssigneeUniversity of North Texas Health Science Center
InventorsYu-Chieh Wang, Victor J. T. Lin, Ashwini Zolekar, Kyle A. Emmitte, Nigam M. Mishra, Jin Liu
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Abstract
In one aspect, the present disclosure provides GlcNAc-Asn analogs of the formula (I): wherein the variables are as defined herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of using the compounds disclosed herein. Additionally, the present disclosure also provides methods of treating cancer comprising inhibiting NGLY1.
Claims11
A method of treating a cancer in a patient, wherein the cancer has an upregulation of NGLY1, comprising administering to the patient a therapeutically effective amount of an inhibitor of N-glycanase 1 (NGLY1), wherein said inhibitor of NGLY1 is a compound of formula:
- wherein:
- R1 is a thiol-reactive group;
- R2 is hydrogen, alkyl(C≤6), substituted alkyl(C≤6), or —C(O)NR7R8;
- wherein:
- R7 and R8 are each independently hydrogen, alkyl(C≤6), or substituted alkyl(C≤6);
- or
- R7 and R8 when taken together are heterocycloalkyl(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
- Y1 is a covalent bond, alkanediyl(C≤6), or substituted alkanediyl(C≤6);
- R3 is alkyl(C≤6) or substituted alkyl(C≤6);
- R4 and R5 are each independently hydrogen, hydroxy, or —OC(O)R9;
- wherein:
- R9 is hydrogen, alkyl(C≤6) or substituted alkyl(C≤6);
- and
- R6 is hydrogen, —OC(O)R10, —NR11C(O)R10, —NR11(CH2)mR10, —NR12R13, or —O(CH2)mR10;
- wherein:
- m is 0, 1, or 2;
- R10 is alkyl(C≤8), cycloalkyl(C≤8), heterocycloalkyl(C≤8), aryl(C≤12), heteroaryl(C≤12), or a substituted version of any of these groups;
- R11 is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6);
- R12 and R13 when taken together are heterocycloalkyl(C≤8), heteroaryl(C≤12), or a substituted version of any of these groups;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.