COMBINATION THERAPY USING A CHEMOKINE RECEPTOR 2 (CCR2) ANTAGONIST AND A PD-1/PD-L1 INHIBITOR
The present disclosure is drawn to the combination therapy of a Chemokine Receptor 2 (CCR2) antagonist and a PD-1 and/or PD-L1 inhibitor in the treatment of cancer.
1 . A method of treating colorectal cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor to the subject, wherein the CCR2 chemokine receptor antagonist has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X 3 and X 4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —NO 2 , —C(O)R 18 , —CO 2 R 18 , —C(O)NR 18 R 19 , —OR 18 , —OC(O)R 19 , —OC(O)NR 18 R 19 , —NO 2 , —NR 18 C(O)R 19 , —NR 18 C(O)NR 19 R 20 , —NR 18 R 19 , —NR 18 CO 2 R 19 , —NR 18 S(O) 2 R 19 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 18 R 19 , substituted or unsubstituted C 6-10 aryl, substituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 18 , R 19 , and R 20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R 18 and R 19 , R 19 and R 20 , or R 18 and R 20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y 9 is selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OR 21 , —CO 2 R 21 , —OC(O)R 21 , —OC(O)NR 21 R 22 , —C(O)NR 21 R 22 , —C(O)R 21 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 C(O) 2 R 22 , —NR 21 S(O) 2 R 22 , —NR 21 C(O)NR 22 R 23 , substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 21 , R 22 , and R 23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R 21 and R 22 , R 22 and R 23 , or R 21 and R 23 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and
Y 11 is —CH—, —N—, and —N + (O) − —.
2 . The method of claim 1 , wherein:
X 4 and X 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, and C 1-8 haloalkyl; and
Y 9 is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-8 alkyl.
3 . The method of claim 1 , wherein:
X 3 is selected from the group consisting of halogen, C 1-8 alkyl, and C 1-8 haloalkyl;
X 4 is selected from the group consisting of halogen and C 1-8 alkyl;
Y 9 is selected from the group consisting of halogen and C 1-8 alkyl; and
Y 11 is —CH— or —N—.
4 . The method of claim 1 , wherein:
X 3 is C 1-8 haloalkyl;
X 4 is selected from the group consisting of halogen and C 1-8 alkyl;
Y 9 is selected from the group consisting of halogen and C 1-8 alkyl; and
Y 11 is —CH— or —N—.
5 . The method of claim 1 , wherein:
X 3 is CF 3 ;
X 4 is Cl or CH 3 ;
Y 9 is Cl or CH 3 ; and
Y 11 is —CH— or —N—.
6 . The method of claim 1 , wherein the CCR2 chemokine receptor antagonist is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
7 . The method of claim 1 , wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.
8 . The method of claim 1 , wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.
9 . The method of claim 1 , wherein the CCR2 chemokine receptor antagonist is
or a pharmaceutically acceptable salt thereof.
10 . The method of claim 1 , wherein the PD-1 and/or PD-L1 inhibitor is a PD-1 inhibitor.
11 . The method of claim 10 , wherein the PD-1 inhibitor is pembrolizumab, nivolumab, or pidilizumab.
12 . The method of claim 1 , wherein the PD-1 and/or PD-L1 inhibitor is a PD-L1 inhibitor.
13 . The method of claim 12 , wherein the PD-L1 inhibitor is durvalumab, atezolizumab, or avelumab.
14 . The method of claim 6 , wherein the PD-1 and/or PD-L1 inhibitor is pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab.
15 . The method of claim 1 , wherein the administration reduces tumor size.
16 . The method of claim 1 , wherein the administration increases a ratio of CD8 T cells to M-MDSCs in a tumor microenvironment.
17 . The method of claim 1 , wherein the subject is a human subject.
18 . A kit comprising a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor, with instruction for effective administration to a subject having a colorectal cancer, wherein the CCR2 chemokine receptor antagonist has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
X 3 and X 4 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —NO 2 , —C(O)R 18 , —CO 2 R 18 , —C(O)NR 18 R 19 , —OR 18 , —OC(O)R 19 , —OC(O)NR 18 R 19 , —NO 2 , —NR 18 C(O)R 19 , —NR 18 C(O)NR 19 R 20 , —NR 18 R 19 , —NR 18 CO 2 R 19 , —NR 18 S(O) 2 R 19 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 18 R 19 , substituted or unsubstituted C 6-10 aryl, substituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 18 , R 19 , and R 20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R 18 and R 19 , R 19 and R 20 , or R 18 and R 20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;
Y 9 is selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OR 21 , —CO 2 R 21 , —OC(O)R 21 , —OC(O)NR 21 R 22 , —C(O)NR 21 R 22 , —C(O)R 21 , —SR 21 , —S(O)R 21 , —S(O) 2 R 21 , —NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 C(O) 2 R 22 , —NR 21 S(O) 2 R 22 , —NR 21 C(O)NR 22 R 23 , substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
R 21 , R 22 , and R 23 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; or
R 21 and R 22 , R 22 and R 23 , or R 21 and R 23 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and
Y 11 is —CH—, —N—, and —N + (O) − —.
19 . The kit of claim 18 , wherein the CCR2 chemokine receptor antagonist is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
20 . The kit of claim 18 , wherein the PD-1 and/or PD-L1 inhibitor is pembrolizumab, nivolumab, or pidilizumab.