Inhibiting interaction between the HIF-1ALPHA and p300/CBP with hydrogen bond surrogate-based helices

Patent metadata

Field	Value
Publication number	US-9399666-B2
Application number	US-200913119108-A
Country	US
Kind code	B2
Filing date	Sep 18, 2009
Priority date	Sep 18, 2008
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

The present invention relates to peptides having one or more stable, internally constrained α-helices, and that include a sequence that mimics at least a portion of the C-terminal transactivation domain of HIF-1α. Also disclosed are pharmaceutical compositions containing these peptides and methods of using these peptides, for example to reduce gene transcription, treat or prevent disorders mediated by interaction of HIF-1α with CREB-binding protein and/or p300, reduce or prevent angiogenesis in a tissue, induce apoptosis, decrease cell survival and/or proliferation, and identify potential ligands of CREB-binding protein and/or p300.

First claim

What is clamied is:

1. A peptide of formula I:

wherein
is a single or double carbon-carbon bond, wherein the double carbon-carbon bond is cis or trans;
each n is independently 1 or 2;
m is zero or any positive integer;
R 1 is an amino acid, a peptide, —OR 4 , —CH 2 NH 2 , an alkyl group, an aryl group, or hydrogen, wherein R 4 is alkyl or aryl;
or R 1 has the formula:

 wherein A 5 is a peptide, an amino acid residue, an acyl group, or hydrogen; and each R 5 is independently an amino acid side chain, hydrogen, an alkyl group, or an aryl group;
R 2 is hydrogen, an amino acid side chain, an alkyl group, or an aryl group;
R 3 is a peptide, —OR 6 , —N(R 7 ) 2 , an alkyl group, an aryl group, or hydrogen, wherein R 6 is an alkyl group or an aryl group and each R 7 is independently an amino acid side chain, hydrogen, an alkyl group, or an aryl group; and:
(i) A 1 is Thr; A 2 is Ser or Ala; A 3 is Tyr or Ala; and A 4 comprises the formula X 1 X 2 X 3 X 4 X 5 X 6 X 7 , wherein X 1 is Asp or Asn; X 2 is Val, Cys, or Ala; X 3 is Glu or Gln; X 4 is Val or Tyr; X 5 is Asn or Arg; X 6 is Ala; and X 7 is Arg or absent; or
(ii) A 1 and A 2 are independently Glu or Gln; A 3 is Leu; and A 4 comprises the formula LRX 8 LX 9 , where L is Leu, R is Arg, X 8 is Ala or Tyr, and X 9 is Asp or Asn; and

wherein the peptide modulates the interaction between HIF-1α C-TAD and the p300/CBP CH1 domain,
with the proviso that the peptide sequence does not consist of the sequence Thr-Ala-Ala-Asp-Cys-Glu-Tyr-Asn-Ala-Arg-NH 2 (SEQ ID NO: 123).

2. The peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

wherein R 2 is hydrogen, an amino acid side chain, an alkyl group, or an aryl group.

3. A pharmaceutical composition comprising a peptide according to claim 1 and a pharmaceutically acceptable vehicle.

4. The peptide according to claim 1 , wherein each n is 1.

5. The peptide according to claim 1 , wherein one n is 1 and one n is 2.

6. The peptide according to claim 1 , wherein each n is 2.

Assignees

• Arora Paramjit S
• Olenyuk Bogdan
• Chapman Ross N
• Henchey Laura
• Block Katherine M
• Univ New York
• Univ Arizona

Inventors

• Arora Paramjit S
• Olenyuk Bogdan
• Chapman Ross N
• Henchey Laura
• Block Katherine M

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title