ASH1L degraders and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11786602-B2
Application number	US-202117468308-A
Country	US
Kind code	B2
Filing date	Sep 7, 2021
Priority date	Nov 10, 2017
Publication date	Oct 17, 2023
Grant date	Oct 17, 2023

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

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

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

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

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

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

8. The composition 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 composition of claim 1 , wherein the Ligase Ligand is selected from:

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

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

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

13. The composition 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 composition 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

wherein m is 6-10, wherein n is 0,
wherein k is 1, and wherein X is O.

15. The composition 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 composition of claim 15 , 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)

Assignees

• Univ Michigan Regents

Inventors

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

Classifications

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title