ASH1L degraders and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-12285490-B2
Application number	US-202318488912-A
Country	US
Kind code	B2
Filing date	Oct 17, 2023
Priority date	Nov 10, 2017
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

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.

First claim

The invention claimed is:

1. A method of treating cancer comprising administering to a subject suffering from cancer with 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 R 1 is selected from

wherein R 9 and R 10 , when present in an R 1 substituent, are independently selected from H, CH 3 , F, CFH 2 , CF 2 H, CF 3 , and OH;
wherein R 8 , when present in an R 1 substituent, is selected from

wherein R 11 , when present in an R 8 substituent, is selected from

wherein R 2 -R 5 and R 7 are independently selected from H, halogen, CH 3 , OH, SH, NH 2 , CN, CF 3 , CCl 3 , —CH 2 —CH 3 , —CH 2 —OH, —CH 2 NH 2 , CH 3 SH, CH 2 Cl, CH 2 Br, CH 2 F, CHF 2 , CH 2 CN, CH 2 CF 3 , and CH 2 Cl 3 ;
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.

2. The method of claim 1 , wherein the Ligase Ligand is capable of binding von Hippel-Lindau (VHL) E3 ligase.

3. The method of claim 2 , wherein the Ligase Ligand comprises a hydroxyproline moiety.

4. The method of claim 3 , wherein the Ligase Ligand comprises

5. The method of claim 1 , wherein the Ligase Ligand is capable of binding a cereblon E3 ubiquitin ligase.

6. The method of claim 5 , wherein the Ligase Ligand comprises a thalidomide, lenalidomide, or pomalidomide moiety.

7. The method of claim 5 , wherein the Ligase Ligand is selected from:

8. The method of claim 1 , wherein the Ligase Ligand is capable of binding a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase or IAP E3 ubiquitin ligase.

9. The method of claim 1 , wherein the Ligase Ligand is selected from:

10. The method of claim 1 , wherein Z is S and X is CH.

11. The method of claim 1 , wherein R 7 is H or halogen.

12. The method of claim 1 , wherein R 2 -R 5 are H.

13. The method of claim 1 , wherein R 1 is selected from

wherein R 9 is selected from H and CH 3 , and R 10 is H, when present in an R 1 substituent;
wherein R 8 , when present in an R 1 substituent, is selected from

 and
wherein R 11 , when present in an R 8 substituent, is selected from

14. The method of claim 1 , wherein:
(i)

 wherein n is 0, and Linker is

 wherein X is O, wherein m is 1, wherein n is 2-4;
(ii)

 wherein n is 0, and Linker is

 wherein X is O, wherein m is 1, wherein n is 2-4, and wherein k is 1-2;
(iii)

 wherein n is 0, and Linker is

 wherein n is 2-4;
(iv) A is

 wherein n is 0, and Linker is

 wherein n is 1, wherein m is 1 or 2, wherein X is O, wherein k is 0;
(v) A is

 wherein n is 0 and Linker is

 wherein n is 5-6, wherein m is 1, wherein X is O;
(vi) A is

 wherein n is 0, and Linker is

 wherein n is 6-10; or
(vii) A is

 wherein n is 0, and Linker is

 X=O, NH or CH 2 , wherein m is 6-10, wherein n is 0, wherein k is 1, and wherein X is O.

15. The method of claim 1 ,
wherein X is CH;
wherein Z is S;
wherein R 7 is H or halogen;
wherein R 2 -R 5 are H;

R 1 is selected from

wherein R 9 is selected from H and CH 3 , and R 10 is H, when present in an R 1 substituent;
wherein R 8 , when present in an R 1 substituent, is selected from

 and
wherein R 11 , when present in an R 8 substituent, is selected from

wherein A is

wherein Ligase Ligand is selected from

 and
wherein Linker is a functional group tethering the Ligase Ligand to A;
or a salt thereof.

16. The method of claim 1 , wherein:
(i)

 wherein n is 0, and Linker is

 wherein X is O, wherein m is 1, wherein n is 2-4;
(ii)

 wherein n is 0, and Linker is

Assignees

• Univ Michigan Regents

Inventors

• Grembecka Jolanta
• Klossowski Szymon
• Deng Jing
• Cierpicki Tomasz
• Li Hao
• Miao Hongzhi
• Purohit Trupta
• Kim Eungi
• Chen Dong

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K47/556

  enzyme catalyzed therapeutic agent [ECTA] · CPC title