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Stabilization of hypoxia inducible factor (HIF) alpha

a technology of inducible factor and stabilization factor, which is applied in the direction of peptide/protein ingredients, chemical treatment enzyme inactivation, peptide sources, etc., can solve the problems of chronic ischemia, recurrence of tias, congestive heart failure and systemic hypotension, etc., to prevent tissue damage, reduce or prevent tissue damage, and treat or prevent the development or persistence of ischemic conditions

Inactive Publication Date: 2003-09-18
FIBROGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0092] FIGS. 10A and 10B show improvement in cardiac performance following myocardial infarction in animals treated with a compound of the invention relative to untreated controls. FIG. 10A shows changes in the left ventricular ejection fraction in a group treated with a compound of the invention relative to an untreated group at time intervals following induced myocardial infarction. FIG. 10B shows changes in the fractional shortening in a group treated with a compound of the invention relative to an untreated group at time intervals following induced myocardial infarction.
[0097] FIGS. 15A and 15B show improved healing of chronic wounds in animals treated with a compound of the invention relative to untreated controls. FIG. 15A shows increased epithelialization and formation of granulation tissue in treated animals relative to untreated controls 7 and 10 days after induction of wounds. FIG. 15B shows no difference in peak-peak distance within the scar in treated animals relative to untreated controls.

Problems solved by technology

If the decrease in perfusion is prolonged or severe, however, chronic ischemia can also be associated with an infarct.
Myocardial infarction, which often involves coronary artery blockage due to thrombosis, arterial wall vasospasms, or viral infection of the heart, can lead to congestive heart failure and systemic hypotension.
While the symptoms of TIAs are temporary and reversible, TIAs tend to recur and are often followed by a stroke.
Ischemic and hypoxic disorders are a major cause of morbidity and mortality.
Further, an estimated five million Americans suffer from venous thrombosis every year, and approximately 600,000 of these cases result in pulmonary embolism.
Other medications, including digoxin, diuretics, aminone, .beta.-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors, are used to stabilize the condition, but none of these therapies directly address the tissue damage produced by the ischemia and hypoxia.
Such conditions may reduce blood flow, producing a state of hypoperfusion to an organ or tissue, or block blood flow completely.
Ischemic conditions may also result when individuals are placed under general anesthesia, and can cause tissue damage in organs prepared for transplant.

Method used

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  • Stabilization of hypoxia inducible factor (HIF) alpha
  • Stabilization of hypoxia inducible factor (HIF) alpha
  • Stabilization of hypoxia inducible factor (HIF) alpha

Examples

Experimental program
Comparison scheme
Effect test

example 1

HIF.alpha. Stabilization in Cells in vitro

[0240] Human cells derived from adenovirus-transformed fetal kidney epithelium (293A), cervical epithelial adenocarcinoma (HeLa), hepatocellular carcinoma (Hep3B), foreskin fibroblast (HFF), mammary gland epithelial adenocarcinoma (MCF7), umbilical vein endothelium (HUVEC), microvascular endothelium (HMEC-1), squamous carcinoma (SSC-25), lung fibroblast (HLF), and venous endothelium (AG10774B) tissues (see, e.g., American Type Culture Collection, Manassas Va.; and Qbiogene, Carlsbad Calif.) were separately seeded into 35 mm culture dishes and grown at 37.degree. C., 20% O.sub.2, 5% CO.sub.2 in media as follows: HeLa cells in Dulbecco's Modification of Eagle's Medium (DMEM), 2% fetal bovine serum (FBS); HFF and HLF cells in DMEM, 10% FBS; 293A cells in DMEM, 5% FBS; HUVEC and AG10774B cells in Endothelial Growth Media (EGM-2; BioWhittaker, Inc., Walkersville Md.); and HMEC-1 in RPMI 1640, 10%FBS; and Hep3B cells in Minimal Essential Medium (M...

example 2

Effect on Oxygen Consumption

[0244] Oxygen Sensor cell culture plates (BD Biosciences, Bedford Mass.) contain a ruthenium complex which is more fluorescent in the absence of oxygen. Therefore, the fluorescent read-out is increased by the presence of oxygen-consuming cells in the plate, which change the equilibrium to lower oxygen saturation and higher fluorescence. A compound that stabilizes HIF by inhibiting hydroxylation is expected to decrease oxygen consumption by decreasing oxygen consumed by the hydroxylation event itself and / or by shifting cellular metabolism from aerobic to anaerobic energy production.

[0245] Human cells derived from adenovirus-transformed fetal kidney epithelium (293A) or cervical epithelial adenocarcinoma (HeLa) (American Type Culture Collection) were grown to confluence in media (high glucose DMEM (Mediatech, Inc., Herndon Va.), 1% penicillin / streptomycin mixture (Mediatech), 1% fetal bovine serum) at 37.degree. C., 10% CO.sub.2. Cells were collected and re...

example 3

Expression of HIF-Regulated Genes in vitro

[0248] Conditioned media collected from cell cultures grown as in Example 1 was analyzed for vascular endothelial growth factor (VEGF) expression using a QUANTIKINE immunoassay (R&D Systems) according to the manufacturer's instructions. As seen in FIG. 4A, fibroblasts (HFF), epithelial cells (293A), and hepatocytes (Hep3B) treated with various compounds of the invention (one of compounds A, B, C, H, K, L, Q, and a prodrug of compound V [pV]) showed an increase in VEGF expression (FIG. 4A). Values on the y-axis represent fold-induction relative to control and are reported on a log.sub.2 scale, such that a value of 1 represents 2-fold induction.

[0249] Alternatively, human cells derived from adenovirus-transformed fetal kidney epithelium (293A) were cultured in DMEM, 5% FBS, 1% Penicillin-Streptomycin at 37.degree. C. and 10% CO.sub.2. After 48 hours, the cells were harvested and were plated confluent in 35 mm culture dishes in regular culture ...

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Abstract

The present invention relates to methods of stabilizing the alpha subunit of hypoxia inducible factor (HIF). The invention further relates to methods of preventing, pretreating, or treating conditions associated with HIF, including ischemic and hypoxic conditions. Compounds for use in these methods are also provided.

Description

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 60 / 337,082, filed on Dec. 6, 2001; U.S. Provisional Application Serial No. 60 / 359,683, filed on Feb. 25, 2002; U.S. Provisional Application Serial No. 60 / 349,659, filed on Jan. 16, 2002; and U.S. Provisional Application Serial No. 60 / 386,488, filed on Jun. 5, 2002, each of which is incorporated by reference herein in its entirety.[0002] The present invention relates to methods of stabilizing the alpha subunit of hypoxia inducible factor (HIF) and to compounds that can be used in these methods.[0003] An early response to tissue hypoxia is induction of hypoxia inducible factor (HIF), a basic helix-loop-helix (bHLH) PAS (Per / Arnt / Sim) transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentration. HIF is a heterodimer containing an oxygen-regulated alpha subunit (HIF.alpha.) and a constitutively expressed beta subunit (HIF.beta.), also known ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/00A61K31/44G01N33/50A61K31/4418A61K31/47A61K31/472A61K31/4745A61K31/496A61K31/555A61K31/63A61K33/26A61K38/00A61K38/17A61K38/22A61K45/00A61K45/06A61P1/04A61P1/16A61P3/10A61P7/06A61P9/00A61P9/08A61P9/10A61P9/12A61P11/00A61P17/02A61P25/00A61P25/08A61P43/00C07K14/47C07K14/505C12N9/99C12N15/09C12Q1/02C12Q1/68G01N33/15
CPCA61K31/00A61K31/47A61K31/4738A61K31/63A61K31/4745C07K14/4702C07K14/505G01N33/746A61K31/472A61K38/1709A61K31/17A61K31/4375A61K31/44A61K31/4418A61K31/496A61P1/04A61P1/16A61P11/00A61P13/12A61P17/02A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00A61P31/00A61P35/00A61P37/00A61P37/04A61P39/00A61P43/00A61P7/00A61P7/06A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P3/10
Inventor GUENZLER-PUKALL, VOLKMARNEFF, THOMAS B.WANG, QINGJIANAREND, MICHAEL P.FLIPPIN, LEE A.MELEKHOV, ALEX
Owner FIBROGEN INC
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