3-substituted piperidine compounds for Cbl-b inhibition, and use thereof
Compounds, compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising a Cbl-b inhibitor and a cancer vaccine, as well as methods for treating cancer using a Cbl-b inhibitor and a cancer vaccine; and pharmaceutical compositions comprising a Cbl-b inhibitor and an oncolytic virus, as well as methods for treating cancer using a Cbl-b inhibitor and an oncolytic virus.
1 . A compound selected from
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or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
2 . A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
3 . A method of modulating activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, wherein the Cbl-b inhibitor is a compound of claim 1 .
4 . The method of claim 3 , wherein the immune cell comprises a T-cell, a B-cell, or a natural killer (NK)-cell.
5 . The method of claim 3 , wherein the immune cell has been or is isolated from a blood sample from a mammalian subject.
6 . The method of claim 3 , wherein the immune cell is a tumor infiltrating lymphocyte (TIL) that has been or is isolated from a tumor of a mammalian subject with cancer.
7 . The method of claim 3 , wherein the immune cell comprises a T-cell, and wherein modulating activity of the T-cell comprises one or more of increased T-cell activation, increased T-cell proliferation, decreased T-cell exhaustion, and decreased T-cell tolerance.
8 . The method of claim 7 , wherein increased T-cell activation comprises increased production of a cytokine.
9 . The method of claim 8 , wherein the cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF.
10 . The method of claim 7 , wherein increased T-cell activation comprises increased cell surface expression of one or more T-cell activation markers.
11 . The method of claim 10 , wherein the T-cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4.
12 . The method of claim 7 , wherein the T-cell has been or is in contact with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody.
13 . The method of claim 7 , further comprising culturing the immune cell with IL-2 alone or in combination with an anti-CD3 antibody and/or an anti-CD28 antibody.
14 . The method of claim 3 , wherein the immune cell comprises a NK-cell, and wherein modulating activity of an NK-cell comprises increased NK-cell activation.
15 . The method of claim 14 , wherein increased NK-cell activation comprises increased production of a cytokine.
16 . The method of claim 15 , wherein the cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β.
17 . The method of claim 3 , wherein the immune cell comprises a B-cell, and wherein modulating activity of a B-cell comprises increased B-cell activation, optionally wherein increased B-cell activation comprises increased expression of CD69.
18 . The method of claim 3 , wherein the immune cell is a human immune cell.
19 . The method of claim 3 , wherein the immune cell comprises a recombinant chimeric receptor.
20 . The method of claim 19 , wherein the recombinant chimeric receptor is a chimeric antigen receptor.
21 . A method of producing a modified immune cell, comprising culturing a cell population containing an immune cell in the presence of an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, thereby producing the modified immune cell, wherein the Cbl-b inhibitor is a compound of claim 1 .
22 . A modified immune cell comprising a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
23 . An isolated modified immune cell, wherein the immune cell has been contacted or is in contact with a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
24 . A method of modulating the immune response, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to modulate the immune response in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
25 . A method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit Cbl-b activity in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
26 . A method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to treat the cancer responsive to inhibition of Cbl-b activity, wherein the Cbl-b inhibitor is a compound of claim 1 .
27 . A method of inhibiting abnormal cell proliferation, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit abnormal cell proliferation in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
28 . A cell culture composition comprising a cell population containing an immune cell and a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
29 . A pharmaceutical composition comprising a Cbl-b inhibitor and one or both of an adjuvant and an antigen, wherein the Cbl-b inhibitor is a compound of claim 1 .
30 . A kit comprising a cell culture composition comprising a cell population containing an immune cell and a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
31 . A method for treating a disease or condition associated with Cbl-b activity, the method comprising administering a Cbl-b inhibitor to an individual in need thereof, wherein the Cbl-b inhibitor is a compound of claim 1 .
32 . A method of treating cancer, the method comprising
administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 , and
administering to the individual an effective amount of an additional therapeutic agent.
33 . A method of treating cancer, the method comprising
administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 , and
administering to the individual an effective amount of radiation therapy.
34 . A method of immunizing, the method comprising
administering to an individual in need thereof an effective amount of a small molecule Cbl-b inhibitor of claim 1 , and
administering to the individual an effective amount of a vaccine.
35 . A method of treating cancer, the method comprising
administering to an individual with cancer an effective amount of a small molecule Cbl-b inhibitor of claim 1 , and
administering to the individual an effective amount of an oncolytic virus.
36 . A method of treating cancer, the method comprising
administering to an individual with cancer an effective amount of a compound of claim 1 , and
administering to the individual an effective amount of a therapeutic cancer vaccine; or
administering to the individual an effective amount of an oncolytic virus.
37 . A pharmaceutical composition comprising a cancer vaccine and a small molecule Cbl-b inhibitor of claim 1 , optionally wherein the composition further comprises a pharmaceutically acceptable excipient.
38 . A pharmaceutical composition comprising an oncolytic virus and a small molecule Cbl-b inhibitor of claim 1 , optionally wherein the composition further comprises a pharmaceutically acceptable excipient.
39 . A kit for treating cancer, the kit comprising
(a) a small molecule Cbl-b inhibitor of claim 1 ;
(b) an oncolytic virus;
(c) instructions for administration of an effective amount of the Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.
40 . A kit for treating cancer, the kit comprising
(a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor of claim 1 and an oncolytic virus; and
(b) instructions for administration of an effective amount of the pharmaceutical composition comprising the small molecule Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.