Aryl hydrocarbon receptor (ahr) activator compounds as cancer therapeutics

Patent metadata

Field	Value
Publication number	US-2022017524-A1
Application number	US-201917293255-A
Country	US
Kind code	A1
Filing date	Nov 14, 2019
Priority date	Nov 14, 2018
Publication date	Jan 20, 2022
Grant date	—

Abstract

The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of cancers, particularly cancers that exhibit elevated expression of FOXA1 and/or FOXA1 gene targets, such as certain breast, liver and/or prostate cancers, including luminal and/or ER-positive forms of breast cancer. Three previously identified adenosine receptor antagonists, CGS-15943, MRS-1220 and SCH-58261, as well as furan ring moiety-possessing derivatives of CGS-15943 are specifically provided for killing cancer cells in a manner that appears to involve activation of the aryl hydrocarbon receptor (AHR) by such compounds. The instant disclosure therefore provides for selecting and/or administering CGS-15943, MRS-1220, SCH-58261 and/or a furan-possessing derivative of CGS-15943, MRS-1220 and/or SCH-58261 as a therapeutic agent to target a cancer cell and/or subject having or at risk of developing a cancer. Methods and compositions for therapies that include such compounds are also provided

First claim

1 . A compound having a structure of formula I:

wherein:
R 1 , R 2 , and R 3 independently represent H or Me, provided that only one of R 1 , R 2 , and R 3 may represent methyl, or wherein R 2 , and R 3 together with the other atoms to which they are bound form an optionally substituted phenyl group;
R 4 represents H, methyl, or NR 5 R 6 wherein R 5 and R 6 independently represent H, methyl, or phenyl, provided that only one of R 5 and R 6 may represent phenyl;
and wherein R 7 , R 8 , and R 9 independently represent H, F, Cl, Br, methoxy, or optionally substituted C1-C3 alkyl,
X represents O or N—R 10 , wherein R 10 represents H or methyl;
X 1 represents C═O or CR 4 ;
X 2 represents N or NH;
and X 3 represents CR 7 or N, provided that X 2 represents NH when X 1 represents C═O, at least one of R 7 , R 8 , and R 9 represents F, Cl, Br, methoxy, or optionally substituted C1-C3 alkyl;
and further provided that if R 1 , R 2 and R 3 independently represent H and R 8 represents Cl, R 4 cannot represent NR 5 R 6 wherein R 5 and R 6 both represent H;
or a pharmaceutically acceptable salt, ester, amide, prodrug or stereoisomer thereof.

2 . The compound of claim 1 , wherein R 1 , R 2 , and R 3 independently represent H.

3 . The compound of claim 1 , wherein R 1 represents methyl and R 2 and R 3 each represents H.

4 . The compound of claim 1 , wherein R 3 represents methyl and R 1 and R 2 each represents H.

5 . The compound of claim 1 , wherein both R 1 and R 3 represent methyl and R 2 represents H.

6 . The compound of claim 1 , wherein R 2 , and R 3 together with the other atoms to which they are bound form an optionally substituted phenyl group.

7 . The compound of claim 1 , wherein:
R 4 is H; R 4 represents methyl; R 4 represents NR 5 R 6 , R 5 represents H and R 6 represents Me; R 4 represents NR 5 R 6 , and R 5 and R 6 represent Me; R 4 represents NR 5 R 6 , R 5 represents H and R 6 represents phenyl; R 4 represents NR 5 R 6 , R 5 represents methyl and R 6 represents phenyl; R 8 represents Cl and R 7 and R 9 each represents H; R 8 represents F and R 7 and R 9 each represents H; R 8 represents Br and R 7 and R 9 each represents H; R 8 represents CF 3 and R 7 and R 9 each represents H; R 8 represents methoxy and R 7 and R 8 each represents H; R 9 represents CF 3 and R 7 and R 8 each represents H; R 9 represents methoxy and R 7 and R 8 each represents H; X represents O; X represents NR 10 , wherein R 10 represents methyl; X 1 represents C═O and X 2 represents NH; and/or X 3 represents N.

8 - 23 . (canceled)

24 . The compound of claim 1 , which is selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, amide, prodrug or stereoisomer thereof.

25 . A method selected from the group consisting of:
A method for selecting a treatment for a subject having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer, the method comprising: (a) identifying a subject as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer; and (b) selecting CGS-15943, a CGS-15943 derivative that possesses a furan ring moiety, MRS-1220, a MRS-1220 derivative that possesses a furan ring moiety, SCH-58261 or a SCH-58261 derivative that possesses a furan ring moiety as a treatment for the subject identified as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer; A method for selecting a treatment for a subject having or at risk of developing a cancer, the method comprising: (a) obtaining a sample from a subject having or at risk of developing a cancer; (b) identifying the presence or absence in the sample of one or more of the following: high FOXA1 mRNA expression levels, high FOXA1 protein expression levels, high mRNA expression levels of a FOXA1 gene target and/or high protein expression levels of a FOXA1 gene target; and (c) selecting CGS-15943, a CGS-15943 derivative that possesses a furan ring moiety, MRS-1220, a MRS-1220 derivative that possesses a furan ring moiety, SCH-58261 or a SCH-58261 derivative that possesses a furan ring moiety as a treatment for the subject if high FOXA1 mRNA expression levels, high FOXA1 protein expression levels, high mRNA expression levels of a FOXA1 gene target and/or high protein expression levels of a FOXA1 gene target are observed in the sample, thereby selecting a treatment for the subject having or at risk of developing a cancer; A method for treating or preventing a luminal and/or estrogen-receptor positive breast cancer in a subject, the method comprising: (a) identifying a subject as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer; and (b) administering CGS-15943, a CGS-15943 derivative that possesses a furan ring moiety, MRS-1220, a MRS-1220 derivative that possesses a furan ring moiety, SCH-58261 or a SCH-58261 derivative that possesses a furan ring moiety to the subject identified as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer, thereby treating or preventing a luminal and/or estrogen-receptor positive breast cancer in the subject; A method for treating or preventing a cancer in a subject, the method comprising: (a) obtaining a sample from a subject having or at risk of developing a cancer; (b) identifying the presence or absence in the sample of one or more of the following: high FOXA1 mRNA expression levels, high FOXA1 protein expression levels, high mRNA expression levels of a FOXA1 gene target and/or high protein expression levels of a FOXA1 gene target; and (c) administering CGS-15943, a CGS-15943 derivative that possesses a furan ring moiety, MRS-1220, a MRS-1220 derivative that possesses a furan ring moiety, SCH-58261 or a SCH-58261 derivative that possesses a furan ring moiety to the subject if high FOXA1 mRNA expression levels, high FOXA1 protein expression levels, high mRNA expression levels of a FOXA1 gene target and/or high protein expression levels of a FOXA1 gene target are observed in the sample, thereby treating or preventing a cancer in the subject; A method for selecting a treatment for a subject having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer, the method comprising: (a) identifying a subject as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer; and (b) selecting an aryl hydrocarbon receptor activator as a treatment for the subject identified as having or at risk of developing a luminal and/or estrogen-receptor positive breast cancer; and A method for selecting a treatment for a subject having or at risk of developing a cancer, the method comprising: (a) obtaining a sample from a subject having or at risk of developing a cancer; (b) identifying the presence or absence in the sample of one or more of the following: high FOXA1 mRNA expression levels, high FOXA1 protein expression levels, high mRNA expression levels of a FOXA1 gene target and/or high protein expression levels of a FOXA1 gene target; and (c) selecting an aryl hydrocarb

Assignees

• Broad Inst Inc
• Dana Farber Cancer Inst Inc
• Inst Carlos Slim De La Salud A C

Inventors

• Corsello Steven
• Spangler Ryan
• Nagari Rohith
• Golub Todd
• Madec Amael

Classifications

• G01N33/57515

  of the breast · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title