METHODS FOR CANCER AND IMMUNOTHERAPY USING PRODRUGS OF GLUTAMINE ANALOGS
The disclosure provides methods of treating cancer in a subject or preventing a relapse or reducing the incidence of relapse of cancer in a subject in remission, comprising administering to the subject: (a) a therapeutically effective amount of an immunotherapeutic agent, e.g., an immune checkpoint blockade therapy, an adoptive cellular therapy, a marrow-infiltrating lymphocytes, an adenosine A2aR inhibitor, or an antibody; and (b) a compound having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2′ , and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
1 . A method of treating cancer in a subject, the method comprising simultaneously or sequentially administering to the subject in need thereof:
(a) a therapeutically effective amount of an immunotherapeutic agent; and
(b) a compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of a bond, —O—, and —(CH 2 ) n —, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 1 is selected from the group consisting of C 1-6 alkyl and substituted C 1-6 alkyl;
R 2 is an amino acid, an N-substituted amino acid, or —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ;
R 2′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;
each R 3 and R 4 are independently H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, —(CR 3 R 4 ) m —NR 5 R 6 , or
m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 5 and R 6 are independently H or alkyl; and
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
2 . The method of claim 1 , wherein X is —CH 2 —.
3 . The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, trimethylammonium, triethylammonium, tri(hydroxyethyl)ammonium, tripropylammonium, and tri(hydroxypropyl)ammonium.
4 . The method of claim 1 , wherein R 2 is selected from the group consisting of —C(═O)—Y—(CR 3 R 4 ) m —NR 5 R 6 , and —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ;
wherein:
Y is —O— or a bond;
m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; and
each R 3 and R 4 is independently H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, aryl or substituted aryl;
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
5 . The method of claim 1 , wherein R 2 is a N-acyl amino acid.
6 . The method of claim 5 , wherein the amino acid is tryptophan.
7 . The method of claim 1 , wherein the compound having formula (I) is a compound having formula (IIA):
wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
Ru is selected from the group consisting of H, methyl, isopropyl, sec-butyl, CH 2 CH(CH 3 ) 2 , benzyl, p-hydroxybenzyl CH 2 OH, CH(OH)CH 3 , CH 2 -3-indoyl, CH 2 COOH, CH 2 CH 2 COOH, —CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , CH 2 SH, CH 2 CH 2 SCH 3 , (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(═NH)NH 2 , and CH 2 -3-imidazoyl;
R 12 is selected from the group consisting of H, C 1-4 alkyl, and —C(═O)R 13 ; and
R 13 is C 1-4 alkyl.
8 . The method of claim 1 , wherein the compound is:
9 . The method of claim 1 , wherein the compound having formula (I) is a compound having formula (III):
wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, and substituted aryl; and
R 10 is C 1-6 alkyl.
10 . The method of claim 9 , wherein the compound selected from the group consisting of:
11 . The method of claim 1 , wherein the immunotherapeutic agent is an immune checkpoint blockade therapy.
12 . The method of claim 13 , wherein the immune checkpoint blockade therapy is selected from the group consisting of PD-1 antagonists, PD-L1 antagonists, CTLA-4 antagonists, LAG3 antagonists, and B7-H3 antagonists, and combinations thereof.
13 . The method of claim 1 , wherein the immunotherapeutic agent is an adoptive cellular therapy.
14 . The method of claim 1 , wherein the immunotherapeutic agent is marrow-infiltrating lymphocytes (MILs).
15 . The method of claim 1 , wherein the immunotherapeutic agent is an adenosine A2aR inhibitor.
16 . The method of claim 1 , wherein the immunotherapeutic agent is a tumor vaccine.
17 . The method of claim 1 , wherein the immunotherapeutic agent is a passive immunotherapy antibody.
18 . The method of claim 17 , wherein the passive immunotherapy antibody is selected from the group consisting of bevacizumab, cetuximab, rituximab, trastuzumab, alemtuzumab, ibritumomab tiuxetan, and panitumumab, and combinations thereof.
19 . The method of claim 1 , wherein the cancer is a newly diagnosed, recurrent, relapsed, and/or refractory cancer selected from the group consisting of celnasopharyngeal cancer, synovial cancer, hepatocellular cancer, renal cancer, cancer of connective tissues, melanoma, lung cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, brain cancer, throat cancer, oral cancer, liver cancer, bone cancer, pancreatic cancer, choriocarcinoma, gastrinoma, pheochromocytoma, prolactinoma, T-cell leukemia/lymphoma, neuroma, von Hippel-Lindau disease, Zollinger-Ellison syndrome, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, ureter cancer, oligodendroglioma, neuroblastoma, meningioma, spinal cord tumor, bone cancer, osteochondroma, chondrosarcoma, Ewing's sarcoma, cancer of unknown primary site, carcinoid, carcinoid of gastrointestinal tract, fibrosarcoma, breast cancer, Paget's disease, cervical cancer, colorectal cancer, rectal cancer, esophagus cancer, gall bladder cancer, head cancer, eye cancer, neck cancer, kidney cancer, Wilms' tumor, liver cancer, Kaposi's sarcoma, prostate cancer, lung cancer, testicular cancer, Hodgkin's disease, non-Hodgkin's lymphoma, oral cancer, skin cancer, mesothelioma, multiple myeloma, ovarian cancer, endocrine pancreatic cancer, glucagonoma, pancreatic cancer, parathyroid cancer, penis cancer, pituitary cancer, soft tissue sarcoma, retinoblastoma, small intestine cancer, stomach cancer, thymus cancer, thyroid cancer, trophoblastic cancer, hydatidiform mole, uterine cancer, endometrial cancer, vagina cancer, vulva cancer, acoustic neuroma, mycosis fungoides, insulinoma, carcinoid syndrome, somatostatinoma, gum cancer, heart cancer, lip cancer, meninges cancer, mouth cancer, nerve cancer, palate cancer, parotid gland cancer, peritoneum cancer, pharynx cancer, pleural cancer, salivary gland cancer, tongue cancer and tonsil cancer.
20 . A method of preventing a relapse or reducing the incidence of relapse of a cancer subject in remission, the method comprising administering to the subject in need thereof a compound, or a pharmaceutically acceptable salt thereof, having formula (I):
wherein:
X is selected from the group consisting of a bond, —O—, and —(CH 2 )—, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 1 is selected from the group consisting of C 1-6 alkyl and substituted C 1-6 alkyl;
R 2 is an amino acid, an N-substituted amino acid, or —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ;
R 2′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;
each R 3 and R 4 are independently H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, substituted aryl, —(CR 3 R 4 ) m —NR 5 R 6 , or
m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R 5 and R 6 are independently H or alkyl; and
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.