CYTOTOXICITY TARGETING CHIMERAS FOR C-C CHEMOKINE RECEPTOR 2-EXPRESSING CELLS
The present disclosure relates to heterobifunctional molecules, referred to as cytotoxicity targeting chimeras (CyTaCs) or antibody recruiting molecules (ARMs) that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. The present disclosure also relates to agents capable of binding to a receptor on a surface of a pathogenic cell and inducing the depletion of the pathogenic cell in a subject for use in the treatment of cancer, inflammatory diseases, autoimmune diseases, viral infection, or bacterial infection.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
T is
R 1 is C 1-4 alkyl or C 3-6 cycloalkyl;
L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), or (L-e):
or a stereoisomer thereof,
wherein:
Ring A and Ring B are each independently C 4-6 cycloalkylene;
L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with —O— or —NR a —;
each R a is independently hydrogen or C 1-3 alkyl; and
L 2a is —O—, —NHC(O)—, or —CH 2 —O—;
or a stereoisomer thereof,
wherein:
Ring A is C 4-6 cycloalkylene or C 7-9 bridged bicyclic cycloalkylene;
L 1b is —CH 2 —NH—C(O)—, —NHC(O)—, or —C(O)NH—;
L 2b is C 6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with —O—, —NR 1b —, —C(O)NR 1b —, or —NR 1b C(O)—; or
L 2b is
wherein n is 1, 2, 3, or 4, and
represents a covalent bond to L 1b ; and
each R 1b is independently hydrogen or C 1-3 alkyl;
or a stereoisomer thereof,
wherein:
L 1c is C 2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —NHC(O)—, or —C(O)NH—;
Ring A is C 4-6 cycloalkylene or C 7-9 bridged bicyclic cycloalkylene; and
L 2c is —O— or a saturated C 2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —NHC(O)—, or —C(O)NH—;
wherein:
L 1d is C 12-30 linear alkylene, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 methylene units are replaced with —NH—, —O—, —C(O)NH—, —NHC(O)—, or —NHC(O)—NH—; or
wherein n is an integer of 3 to 50;
wherein each
represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the T group of Formula (I), and each
represents a covalent bond to the methylene group of Formula (I); and
Y is a bond or a divalent spacer moiety of one to twelve atoms in length.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-i):
or a stereoisomer thereof,
wherein Ring A L 1a , L 2a ,
and are as defined for Formula (L-a).
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-ii):
or a stereoisomer thereof,
wherein L 1a , L 2a ,
and are as defined for Formula (L-a); p is 1 or 2; and m is 1 or 2.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-iii):
or a stereoisomer thereof,
wherein p is 1 or 2; m is 1 or 2; n is 1, 2, or 3; and
are as defined for Formula (L-a).
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a) selected from the group consisting of:
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-b-i):
or a stereoisomer thereof,
wherein L 1b , L 2b ,
and are as defined for Formula (L-b); p is 1 or 2; and m is 1 or 2.
8 . The compound of claim 1 , wherein L is a divalent linker of Formula (L-b) selected from the group consisting of:
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-c-i):
or a stereoisomer thereof,
wherein L 1c , L 2c ,
and are as defined for Formula (L-c); p is 1 or 2; and m is 1 or 2.
10 . The compound of claim 1 , wherein L is a divalent linker of Formula (L-c) selected from the group consisting of
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-d) selected from the group consisting of:
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from a bond; —NH—; —(C 1-12 alkylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—, —(C 3-6 cycloalkylene)-, —(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene; or —(C 2-12 alkenylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—, —(C 3 0.6 cycloalkylene)-, —(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene.
13 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from a bond; —NH—; —(C 1-6 alkylene)-O—; —(C 2-6 alkenylene)-O—; —(C 1-6 alkylene)-C(O)—; —(C 2-6 alkenylene)-C(O)—; phenylene; piperidinylene; —(C 1-6 alkylene)-O-phenylene-; —(C 2-6 alkenylene)-O-piperidinylene; —(C 1-5 alkylene)-NH—, wherein 0, 1, or 2 methylene units are replaced with —O—; —NH—(C 1-5 alkylene)-NH—; —(C 3-6 cycloalkylene)-NH—; —(C 3-6 cycloalkenylene)-NH—; or
wherein Y 1a is a bond, —O—, —NH—, —NHC(O)—, —C(O)NH—, or C 1-3 alkylene; and Y 2a is a bond, —O—, —NH—, —NHC(O)—, —C(O)NH—, or C 1-3 alkylene.
14 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:
15 . The compound of claim 1 , wherein the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.
16 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17 . A method of treating and/or preventing a disease or disorder in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the disease or disorder is selected from a cancer, an inflammatory disease, an autoimmune disease, a viral infection, or a bacterial infection.
18 . The method of claim 17 , wherein the disease or disorder is mediated by chemokine receptor 2 (CCR2) and/or is associated with CCR2-positive pathogenic cells.
19 . The method of claim 17 , wherein the disease is a cancer that is a solid tumor.
20 . The method of claim 17 , wherein the disease or disorder is a cancer selected from leukemia, lymphoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, bladder cancer, or breast cancer.
21 . (canceled)
22 . (canceled)
23 . A method of increasing antibody-dependent cell cytotoxicity (ADCC) of C—C motif chemokine receptor 2 (CCR2)-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the CCR2-binding moiety of the compound binds the CCR2 expressed on the cells.
24 . A method of depleting C—C motif chemokine receptor 2 (CCR2)-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the CCR2-binding moiety of the compound binds the CCR2 expressed on the cells.
25 . (canceled)
26 . The method of claim 20 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
27 . The method of claim 20 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.
28 . (canceled)
29 . (canceled)
30 . The method of claim 20 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
31 . A combination comprising the compound of claim 1 , and an anti-cotinine antibody, or antigen-binding fragment thereof.
32 . The combination of claim 31 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
33 - 36 . (canceled)