Use of small molecule inhibitors to KLF10 for modulation of T regulatory cells and cancer immunotherapy

Patent metadata

Field	Value
Publication number	US-11267807-B2
Application number	US-201615337633-A
Country	US
Kind code	B2
Filing date	Oct 28, 2016
Priority date	Oct 28, 2015
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The invention relates to compositions and methods for inhibiting Krüppel-like Factor 10 (KLF10) for modulation of T regulatory cells and cancer immunotherapy.

First claim

What is claimed is:

1. A composition comprising: an effective amount of an inhibitor of KLF10 in combination with one or more disease antigens, wherein the inhibitor of KLF10 is a compound of formula:

wherein:
(i)
R 2 is selected from H, OH, CH 3 , and OCH 3 ;
R 4 is selected from H, OH, and OCH 3 ;
R 5 is selected from H, CH 3 , and C 2 H 5 ;
X is OC(═O);
R 2 ′ is selected from H and OH;
R 3 ′ is selected from H and OCH 3 ;
R 4 ′ is selected from H, CH 3 , C 2 H 5 , CH 2 (CH 3 ) 2 , OCH 3 , Ph, F, and I;
R 5 ′ is CH 3 , or

wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, or R 5 ′ may be optionally connected; or
(ii)
R 2 is selected from H, OH, CH 3 , and OCH 3 ;
R 4 is selected from H, OH, and OCH 3 ;
R 5 is selected from H, CH 3 , and C 2 H 5 ;
X is OC(═O);
R 2 ′ is selected from H and OH;
R 3 ′ is H;
R 4 ′ is selected from H, CH 3 , C 2 H 5 , CH 2 (CH 3 ) 2 , OCH 3 , Ph, F, and I;
R 5 ′ is OCH 3 , or

wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, or R 5 ′ may be optionally connected.

2. The composition of claim 1 , wherein the compound is

3. A composition comprising: an effective amount of an inhibitor of KLF10 in combination with a vaccine; wherein the inhibitor of KLF10 is a compound of formula:

wherein:
(i)
R 2 is selected from H, OH, CH 3 , and OCH 3 ;
R 4 is selected from H, OH, and OCH 3 ;
R 5 is selected from H, CH 3 , and C 2 H 5 ;
X is OC(═O);
R 2 ′ is selected from H and OH;
R 3 ′ is selected from H and OCH 3 ;
R 4 ′ is selected from H, CH 3 , C 2 H 5 , CH 2 (CH 3 ) 2 , OCH 3 , Ph, F, and I;
R 5 ′ is CH 3 ; or

wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, or R 5 ′ may be optionally connected; or
(ii)
R 2 is selected from H, OH, CH 3 , and OCH 3 ;
R 4 is selected from H, OH, and OCH 3 ;
R 5 is selected from H, CH 3 , and C 2 H 5 ;
X is OC(═O);
R 2 ′ is selected from H and OH;
R 3 ′ is H;
R 4 ′ is selected from H, CH 3 , C 2 H 5 , CH 2 (CH 3 ) 2 , OCH 3 , Ph, F, and I;
R 5 ′ is OCH 3 , or

wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 4 ′, or R 5 ′ may be optionally connected.

4. The composition of claim 1 , wherein the compound is

5. The composition of claim 1 , wherein the compound is

6. The composition of claim 1 , wherein
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH; and R 5 ′ is CH 3 , or OCH 3 ; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, and R 3 ′ is H or OCH 3 .

7. The composition of claim 1 , wherein the compound is

8. The composition of claim 3 , wherein the compound is

9. The composition of claim 3 , wherein the compound is

10. The composition of claim 3 , wherein the compound is

11. The composition of claim 3 , wherein
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH, where R 5 ′ is selected from CH 3 , and OCH 3 ; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, where R 3 ′ is selected from H and OCH 3 .

12. The composition of claim 3 , wherein the compound is

13. A method of modulating an immune response, comprising: administering to a subject an effective amount of a composition of claim 1 .

14. A method of modulating an immune response, comprising: administering to a subject an effective amount of a composition of claim 3 .

15. A method for treating cancer in a subject, comprising: administering to the subject having said cancer a composition of claim 1 .

16. A method for treating cancer in a subject, comprising: administering to the subject having said cancer a composition of claim 3 .

Assignees

• Brigham & Womens Hospital Inc
• Beth Israel Deaconess Medical Ct Inc
• Beth Isreal Deaconess Medical Center Inc

Inventors

• Feinberg Mark
• Khedkar Santosh A

Classifications

• C07C251/86

  having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C217/48

  the carbon skeleton being unsaturated and containing rings · CPC title

• C07C205/45

  the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group · CPC title

• C07C39/15

  with all hydroxy groups on non-condensed rings {, e.g. phenylphenol} · CPC title

• C07C49/84

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title