Bcl6 inhibitors as anticancer agents

Patent metadata

Field	Value
Publication number	US-2016166549-A1
Application number	US-201414899083-A
Country	US
Kind code	A1
Filing date	Jun 16, 2014
Priority date	Jun 17, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

The invention provides compositions and methods for blocking the BCL6 BTB domain with small molecule, non-peptide compounds as disclosed and claimed herein. BCL6 is a transcriptional repressor of the BTB-POZ (brie a brae, tramtrack, broad complex/pox virus zincfinger) family of proteins. It is required for normal development of germinal center (GC) B-cells and is also the most commonly involvedoncogene in diffuse large B-celllymphomas (DLBCLs), and constitutive expression of BCL6 in GC B-cells causes DLBCL in mice.

First claim

1 . A method of disrupting BCL6 BTB domain interactions with corepressors, in B-cells, comprising exposing the B cells to an effective concentration of a compound that blocks the lateral groove of BCL6.

2 . A method of inhibiting DLBCL tumor growth, or causing DLBCL tumor regression, or both, in a mammal, comprising administering to the mammal an effective dose of a compound that blocks the BTB lateral groove of BCL6.

3 . A method of inhibiting transcriptional repression induced by a complex of BCL6 with SMRT or other corepressor proteins in cancer cells, comprising exposing the cancer cells to an effective concentration of a compound that blocks the BTB lateral groove of BCL6.

4 . A method of treatment of a patient afflicted with cancer, comprising administering to the patient an effective dose of a compound that blocks the BTB lateral groove of BCL6.

5 . The method of any one of claims 1 - 4 , wherein the compound that blocks the BTB lateral groove of BCL6 is a compound of formula (I)

wherein a dashed line indicates that a double bond can be present or absent; when a double bond is present, R 3 is absent; R 1 is H, (C1-C6)alkyl, benzyl, 2-propenyl or 2-propynyl, or R 1 is a group of formula —CH 2 CO 2 R or of —CH 2 C(═O)OCH(R)—Ar 1 , wherein R is H or (C1-C6)alkyl, Ar 1 is phenyl substituted with 0, 1, or 2 independently selected substituents from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halo, and (C1-C6)haloalkyl; n=1, 2, or 3; R 3 is H or OH; each of R 4 , R 5 , R 6 and R 7 is independently selected H, F, Cl, or Br; X is O or S; Y is OH or O(C1-C6)alkyl; or a pharmaceutically acceptable salt thereof; provided that when R 1 is H, Y is OH, the double bond indicated by the dashed line is present and R 3 is absent, and n=1, 2, or 3, not all of R 4 , R 5 , R 6 and R 1 are H; and when R 1 is H, methyl, or 2-propenyl, Y is OH, the double bond indicated by the dashed line is present and R 3 is absent, n=1, 2 or 3, and R 4 , R 5 and R 7 are H, R 6 is not bromo.

6 . The method of claim 5 , wherein the compound of formula (I) is any one of

or a pharmaceutically acceptable salt thereof.

7 - 20 . (canceled)

21 . The method of claim 4 , wherein in addition to administration of the compound that blocks the BTB lateral groove of BCL6, an effective amount of a second anticancer agent is administered to the patient.

22 . The method of claim 21 , wherein the second anticancer agent is doxorubicin, vincristine, dexamethasone, mechloretamine, or comprises a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Assignees

• Univ Cornell
• Univ Maryland

Inventors

• Melnick Ari
• Cerchietti Leandro Carlos A
• Cardenas Mariano G
• Xue Fengtian
• Mackerell Alexander D

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4166

  having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/427 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title