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

Patent metadata

Field	Value
Publication number	US-12428410-B2
Application number	US-202217587304-A
Country	US
Kind code	B2
Filing date	Jan 28, 2022
Priority date	Oct 28, 2015
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

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: (i) one or more disease antigens or a vaccine; and (ii) a compound of formula:

wherein:
(a)
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 ;
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(CH 3 ) 2 , OCH 3 , Ph, F, and I; and
R 5 ′ is selected from H, CH 3 , and OCH 3 ; or
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, or
wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, and R 5 ′ may be optionally connected;

or
(b)
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 H;
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 , OCH 3 , Ph, F, and I; and
R 5 ′ is selected from H; or
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, or
wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, and R 5 ′ may be optionally connected.

2. The composition of claim 1 , wherein
a. R 2 is H, R 4 is OCH 3 , R 5 is H, R 2 ′ is OH, R 3 ′ is H, R 4 ′ is H, and R 5 ′ is CH 3 ;
b. R 2 is OCH 3 , R 4 is H, R 5 is H, R 2 ′ is OH, R 3 ′ is H, R 4 ′ is H, and R 5 ′ is CH 3 ;
c. R 2 is OCH 3 , R 4 is OCH 3, R 5 is H, R 2 ′ is OH, R 3 ′ is H, R 4 ′ is H, and R 5 ′ is CH 3 ;
d. R 2 is OCH 3 , R 4 is OCH 3 , R 5 is H, R 2 ′ is OH, R 3 ′ is H, R 4 ′ is H, and R 5 ′ is OCH 3 ; or
e. R 2 is CH 3 , R 4 is H, R 5 is CH 3 , R 2 ′ is OH, R 3 ′ is H, and R 4 ′ and R 5 ′ together are —CH═CH—CH═CH—.

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

4. The composition of claim 1 , wherein:
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 ;
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(CH 3 ) 2 , OCH 3 , Ph, F, and I; and
R 5 ′ is selected from H, CH 3 , and OCH 3 ; or
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, or
wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, and R 5 ′ may be optionally connected.

5. The composition of claim 1 , wherein:
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 H;
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 , OCH 3 , Ph, F, and I; and
R 5 ′ is selected from H; or
R 3 ′ and R 4 ′ can be taken together as CH═CH—CH═CH; or
R 4 ′ and R 5 ′ can be taken together as CH═CH—CH═CH, or
wherein two of R 2 , R 4 , and R 5 may be optionally connected, and two of R 2 ′, R 3 ′, R 4 ′, and R 5 ′ may be optionally connected.

6. The composition of claim 1 , wherein the composition comprises one or more disease antigens.

7. The composition of claim 1 , wherein the composition comprises a vaccine.

8. A method for modulating an immune response in a subject or treating a cancer in a subject or decreasing T regulatory (T-reg) cells at a tumor site or a pathogen infected area of a subject, the method comprising administering an effective amount of a composition of claim 1 to a subject in need thereof.

Assignees

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

Inventors

• Feinberg Mark
• Khedkar Santosh A

Classifications

• 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

• C07C251/86

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