Conjugated chemical inducers of degradation and methods of use

Patent metadata

Field	Value
Publication number	US-12440706-B2
Application number	US-202117239086-A
Country	US
Kind code	B2
Filing date	Apr 23, 2021
Priority date	Oct 24, 2018
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The subject matter described herein is directed to antibody-CIDE conjugates (Ab-CIDEs), to pharmaceutical compositions containing them, and to their use in treating diseases and conditions where targeted protein degradation is beneficial.

First claim

What is claimed is:

1. A conjugate having the chemical structure:
Ab-(L1-D) p ,
wherein,
D is a CIDE having the structure;
E3LB-L2-PB,

wherein:
E3LB is covalently bound to L1 and L2, having the structure of

 wherein indicates the attachment point to L2 and indicates the attachment point to L1;
L2 is a linker covalently bound to E3LB and PB;
PB is a protein binding group covalently bound to L2 and the PB binds BRD4 or Estrogen Receptor alpha (ERα), or variants, mutations, splice variants, indels or fusions thereof;

Ab is an antibody covalently bound to L1;
L1 is a linker covalently bound to the Ab and the E3LB, wherein L1 has the formula selected from the group consisting of:

wherein, R 1 and R 2 are independently selected from H and C 1 -C 6 alkyl, or R 1 and R 2 together with the carbon to which each is attached form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group; R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R 15 is optionally substituted heteroaryl or optionally substituted aryl; and R is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; and
p has a value of from 1 to 8.

2. The conjugate of claim 1 , wherein R 1 and R 2 are each independently hydrogen or methyl.

3. The conjugate of claim 1 , wherein R 1 and R 2 are each methyl.

4. The conjugate of claim 1 , wherein R 2 is methyl.

5. The conjugate of claim 1 , wherein L1 is covalently bound to a cysteine thiol group of the antibody.

6. The conjugate of claim 5 , wherein the structure of L1 covalently bound to the cysteine thiol group of the antibody is selected from the group consisting of:

7. The conjugate of claim 6 , wherein the L1-D to which the antibody is conjugated is selected from the group consisting of:

8. The conjugate of claim 6 , wherein the cysteine of the antibody is engineered.

9. The conjugate of claim 8 , wherein the engineered cysteine is selected from the group consisting of LC-K149C, HC-A140, HC-L174C, and HC—Y373C.

10. The conjugate of claim 1 , wherein p is between 1 and 6.

11. The conjugate of claim 10 , wherein p is 2 or 6.

12. A pharmaceutical composition comprising the conjugate of claim 1 , and at least one pharmaceutical excipient.

13. A method of treating a subject having a condition modulated by the protein bound by the PB of the conjugate of claim 1 , comprising administering an effective amount of the conjugate to said subject.

14. The method of claim 13 , wherein the conjugate is co-administered with at least one additional therapeutic agent.

15. A compound having the formula L1-D, wherein D is a CIDE having the structure;
E3LB-L2-PB,
wherein:
E3LB is covalently bound to L1 and L2,

having the structure of

wherein indicates the attachment point to L2 and indicates the attachment point to L1;
L2 is a linker covalently bound to E3LB and PB; and
PB is a protein binding group covalently bound to L2 and the PB binds BRD4 or Estrogen Receptor alpha (ERα), or variants, mutations, splice variants, indels or fusions thereof; and

L1 is covalently bound to E3LB and has the formula selected from the group consisting of:

wherein, R 1 and R 2 are independently selected from H and C 1 -C 6 alkyl, or R 1 and R 2 together with the carbon to which each is attached form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group; R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R 15 is optionally substituted heteroaryl or optionally substituted aryl; and R is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl.

16. The compound of claim 15 , wherein said compound is selected from the group consisting of:

17. The compound of claim 15 , wherein between 2 and about 6 compounds are linked to an antibody.

Assignees

• Genentech Inc

Inventors

• DRAGOVICH Peter
• Pillow Thomas
• Blake Robert Anthony
• Wertz Ingrid

Classifications

• A61K31/661

  Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title