ASH1L degraders and methods of treatment therewith
AssigneeThe Regents of the University of Michigan
InventorsJolanta Grembecka, Szymon Klossowski, Jing Deng, Tomasz Cierpicki, Hao Li, Hongzhi Miao, Trupta Purohit, EunGi Kim, Dong Chen
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Abstract
Provided herein are small molecules comprising a first domain that binds to ASH1L and a second domain that facilitates ASH1L degradation. In particular, ASH1L-targeting proteolysis targeting chimeras (PROTACs) and methods of use thereof for the treatment of disease (e.g., acute leukemia, solid cancers and other diseases dependent on activity of ASH1L) are provided.
Claims20
A composition comprising a proteolysis targeting chimera (PROTAC) compound capable binding to ASH1L and an E3 ligase complex, the PROTAC compound comprising a structure of:
- wherein X is CH or N;
- wherein Z is S or O;
- wherein R1 is selected from
- wherein R9 and R10, when present in an R1 substituent, are independently selected from H, CH3, F, CFH2, CF2H, CF3, and OH;
- wherein R8, when present in an R1 substituent, is selected from
- wherein R11, when present in an R8 substituent, is selected from
- wherein R2-R5 and R7 are independently selected from H, halogen, CH3, OH, SH, NH2, CN, CF3, CCl3, —CH2—CH3, —CH2—OH, —CH2NH2, CH3SH, CH2Cl, CH2Br, CH2F, CHF2, CH2CN, CH2CF3, and CH2Cl3;
- wherein A is
- wherein Ligase Ligand is a moiety capable of binding to the E3 ligase complex;
- and
- wherein Linker is a functional group tethering the Ligase Ligand to A;
- or a salt thereof.
A method of degrading ASH1L, comprising contacting ASH1L within a cell with an effective amount of a proteolysis targeting chimera (PROTAC) compound capable binding to ASH1L and an E3 ligase complex.
A method of treating cancer comprising administering to a subject a proteolysis targeting chimera (PROTAC) compound capable binding to ASH1L and an E3 ligase complex in an amount effective to inhibit the activity of ASH1L and/or facilitate degradation of ASH1L.
Dependencies are inferred from the claim text.