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), (L-b), (L-c), (L-f), (L-g), (L-h), (L-i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv):
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—;
or a stereoisomer thereof,
wherein:
L 1f is a bond; C 1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with —O—, —NH—, or —C(O)—; or —(C 3-6 cycloalkylene)-NHC(O)—;
L 2f is a bond, —NHC(O)—, —C(O)NH—, or a C 1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with —O—; and
each of Z 1 and Z 2 is independently N or CH;
wherein:
Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms;
L 1g is a bond, —CH 2 —, —NH—, or —O—; and
L 2g is
wherein n is 1, 2, 3, 4, or 5, and
represents a covalent bond to L1g;
or a stereoisomer thereof,
wherein:
each Z 1 is independently N or CH;
L 1h is a bond, —C(O)—, —C(O)—NH—, or —NHC(O)—;
L 2h is C 2-10 linear alkylene or
wherein n is 1, 2, 3, or 4, and
represents a covalent bond to L 1h and
represents a covalent bond to L 3h ;
L 3h is a bond, —C(O) CH 2 —, —O—(C 3-6 cycloalkylene)-O—, or —C(O)NH(CH 2 ) 3 OCH 2 —;
L 4h is a bond, —C(O)—, —CH 2 C(O)—, or —C(O) CH 2 —; and
m is 1, 2, or 3;
wherein:
L 1i is a bond, C 1-12 linear alkylene, or
wherein n is
1, 2, 3, 4, or 5, and
represents a covalent bond to L 3i and
represents a covalent bond to NH;
L 2i is a bond, C 1-12 linear alkylene, or
wherein n is 1, 2, 3, 4, or 5, and
represents a covalent bond to HN; and
L 3i is a bond or —C(O)—;
or a stereoisomer thereof,
wherein:
Z 1 is C, CH, or N;
each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N;
L 1j is —NH—, —C(O)NH—, —NHC(O)—, or —O—;
L 2j is C 1-6 linear alkylene or
wherein n is 1 or 2, and
represents a covalent bond to L 1j ; and
represents a single bond or a double bond;
or a stereoisomer thereof,
wherein:
Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms;
each of Z 1 and Z 2 is independently CH or N;
L 1k is a bond, —C(O)—, —C(O)NH— or —NHC(O)—; and
L 2k is a C 3-8 straight chain alkylene or
wherein n is 1, 2, or 3, and
represents a covalent bond to L 1k ;
or a stereoisomer thereof,
wherein:
Z 1 is CH or N;
m is 1 or 2;
p is 1 or 2;
0, 1, or 2 hydrogen atoms of
are replaced with F;
L 1m is a bond, —C(O)—, —C(O)NH—, —NHC(O)—, —S(O) 2 NH— or —NHS(O) 2 —; and
L 2m is C 3-6 linear alkylene, C 3-6 cycloalkylene, or
wherein
n is 1 or 2, and
represents a covalent bond to L 1m ;
wherein each
represents a covalent bond to the NH group of Formula (I), and each
represents a covalent bond to the methylene group of Formula (I).
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl, and R 3 is methyl.
4 . 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).
5 . 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.
6 . 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).
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker selected from the group consisting of:
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker selected from the group consisting of:
9 . A compound in the following table or a pharmaceutically acceptable salt thereof:
10 . A compound represented by:
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , wherein the compound is represented by:
12 . A pharmaceutical composition comprising (i) a compound of claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient, carrier, or diluent.
13 . A pharmaceutical composition comprising (i) a compound of claim 10 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient, carrier, or diluent.
14 . A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable excipient, carrier, or diluent.
15 . A method of treating a disease or disorder mediated by chemokine receptor 2 (CCR2) and/or is associated with CCR2-positive pathogenic cells 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).
17 . The method of claim 15 , wherein the disease or disorder is a leukemia, lymphoma, myeloma, 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.
18 . A method of treating cancer in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of the compound of claim 10 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the cancer is a leukemia, lymphoma, myeloma, 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, or breast cancer.
19 . The method of claim 18 , wherein the cancer is a leukemia, lymphoma, myeloma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSC), pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, or breast cancer.
20 . The method of claim 18 , wherein the cancer is leukemia.
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 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 10 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 . The method of claim 22 , wherein the CCR2-expressing cells are myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), neutrophils, macrophages, B regulatory cells (Bregs), CD8 regulatory cells, (CD8regs), exhausted T cells, or cancer-associated fibroblasts (CAFs).
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 . 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.
26 . 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.
27 . 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.
28 . A combination comprising the compound of claim 1 and an anti-cotinine antibody, or antigen-binding fragment thereof.
29 . A combination comprising the compound of claim 10 and an anti-cotinine antibody, or antigen-binding fragment thereof.