CYTOTOXICITY TARGETING CHIMERAS FOR CCR2-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:
R 1 is C 1-4 alkyl or C 3-6 cycloalkyl;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is hydrogen or C 1-4 alkyl;
L is a divalent linker of Formula (L-a):
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—;
wherein
represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the quinazoline group of Formula (I), and
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 R 1 is ethyl.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl and R 3 is methyl.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is t-butyl and R 3 is hydrogen.
6 . 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 ,
are as defined for Formula (L-a).
7 . 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 ,
are as defined for Formula (L-a); p is 1 or 2; and m is 1 or 2.
8 . 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).
9 . 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:
10 . 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 3-6 cycloalkylene)-, —(C 3-6 cycloalkenylene)-, 3-to 6-membered heterocycloalkylene, arylene, or heteroarylene.
11 . (canceled)
12 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:
13 . The compound of claim 1 , wherein the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.
14 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15 . 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.
16 . The method of claim 15 , wherein the disease or disorder is mediated by chemokine receptor 2 (CCR2) and/or is associated with CCR2-positive pathogenic cells.
17 . The method of claim 15 , wherein the disease is a cancer that is a solid tumor.
18 . The method of claim 15 , 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, endometrial cancer, bladder cancer, or breast cancer.
19 . (canceled)
20 . (canceled)
21 . 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.
22 . 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.
23 . (canceled)
24 . The method of claim 18 , 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.
25 . The method of claim 18 , 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.
26 . (canceled)
27 . (canceled)
28 . The method of claim 18 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
29 . A combination comprising the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof.
30 . The combination of claim 29 , 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.
31 . The combination of claim 29 , 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.
32 - 34 . (canceled)