Category Archives: Drug Discovery & Therapeutics

ADME-Tox, leads, NCEs, supplements, targets, vaccines, etc.

Drugs for the treatment of cardiac arrest and other shock states

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Summary:

Researchers at The Ohio State University have discovered new drugs for augmenting perfusion pressure administered during cardiopulmonary resuscitation and other shock states. Approximately 450,000 people yearly suffer a cardiac arrest outside the hospital with less than 10% of these patients discharged from the hospital alive, and of these, approximately 60% suffer some form of permanent neurological injury. While epinephrine is used during CPR to enhance perfusion, new drugs are needed to optimize hemodynamics and minimize toxicity. The new drugs discovered at Ohio State include phenylethanolamines and imidazolines, and fluorinated derivatives thereof, which act on adrenergic receptors in patients. These compounds effectively enhance neurological outcome and survival, and decrease ventricular dysrhythmias in patients suffering cardiac arrest and other shock states.

Potential Applications:

This lifesaving drug can be administered after experiencing a traumatic shock like cardiac arrest or other shock states.

Advantages:

  • More effective at optimizing hemodynamics and minimizing toxicity compared to epinephrine which is currently used.
  • Makes use of adrenergic receptors which has been shown to be more effective than CPR alone.

3-D Embryonic Stem Cell GFP-Based Fluorescence Assays for High-Throughput Drug Screening, Bioprocess Development, and Biosensing Applications

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Summary:

Mammalian, live-cell, fluorescent, kinetic assays are common tools for the pharmaceutical industry, for safety evaluation agencies and even for basic science research as these assays are highly suitable for automatic high-throughput screening and they enable the characterization of rapid cellular events. However, fluorescent signals generated in such assays are usually too weak for in situ measurements. Researchers at The Ohio State University have developed a three-dimensional (3-D) cell culture system that out-performs conventional 2-D cultures which lack proper in vivo tissue functions and are inherently prone to error. The higher cell density in 3-D cell culture shows differences in drug cytotoxicity responses as compared with those from the 2-D cell culture assays and also gives a potential for higher signal to noise ratio (SNR). OSU has designed, built and tested a high throughput, real time, bioactivity assay based on the 3-D culture of GFP-expressing embryonic stem (ES) cells, which can increase SNR at least one order of magnitude and minimize errors due to biological system changes caused by cell activities as compared to conventional 2-D cultures. The 3-D ES cell culture system using inexpensive materials can afford parallel, automated, accurate and long-term (more than one week) cell bioactivity assays. This system has the potential for use as high-throughput biosensors, micro-bioreactor arrays for bioprocess optimization, cytotoxicity assays for drug screening and discovery, and media optimization for expanding and differentiating embryonic stem cells.

Potential Applications:

Markets of interest include the pharmaceutical industry, safety evaluation agencies and basic science research. Applications include high-throughput biosensors, micro-bioreactor arrays for bioprocess development, cytotoxicity assays for drug screening and discovery, and process and media optimization for embryonic stem cell expansion and differentiation.

Advantages:

  • Fluorescent signals are stronger thereby allowing for in situ measurements
  • Improved differenciation in drug cytotoxicity responses
  • Higher signal to noise ratio (SNR) by at least 1 order of magnitude
  • Less errors due to biological system changes
  • Inexpensive materials
  • Can perform parallel, automated, accurate and long-term (>1 week) cell bioactivity assays

A Novel Class of Small Molecule Inhibitors of Histone Deactylase for Treatment of Cancer and Cell Proliferative Diseases

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Summary:

Researchers at The Ohio State University have a novel class of small molecule inhibitors of histone deactylase designed to trigger growth arrest, differentiation, and/or apoptosis in many types of tumor cells. Our researchers have discovered that the lack of potency of known histone deacetylase inhibitors is due to a structural motif that interferes with access to the molecular target site on histones. The OSU compounds incorporate the chemical structure necessary to inhibit histone acetylation and thus to treat prostate and possibly other tumors of epithelial origin. The acetylation status of histones plays a major role in regulating gene transcription through modulation of packaging of DNA. The OSU compounds work by reactivating transcription of certain genes in neoplastic cells. Given the transcriptional regulation that results from dosing cells with these inhibitors, they may also act as preventive agents of neoplastic or hyperplastic diseases such as psoriasis.

These compounds are undergoing preclinical testing under the NIH Rapid Access to Interventional Development (RAID) program with the goal of entering into Phase 1 clinical trials within two years.

Potential Applications:

  • Treatment of cancers of epithelial origin such as prostate, breast, ovary, etc
  • Potential treatment for psoriasis and other diseases hallmarked by aberrant cell growth.

Peptide structure nucleation and enhanced binding by chemical constraint

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Summary:

Stabilized peptide structures can be used to bind to target molecules, such as proteins, to influence biological activity. Researchers at Ohio State University have developed a method by which a stabilzed peptide secondary structure and tertiary contacts can be sythesized simutaneously. The addition of a tertiary contact is not possible using the current methods. The current methods use a intramolecular ring closing methathesis (RCM), while this method uses a intermolecular RCM, allowing for greater control.

Potential Applications:

  • Novel therapuetic synthesis
  • New material sythesises using chemical reactions, such as polymerization depending on functional group added

Advantages:

  • Ability to control functionality with tertiary contact
  • Confer functionality and structure in one reaction

Development of a New Class of Anticancer Agents

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Summary:

A new direction for both basic and clinical cancer research involves the study of apoptosis, a type of programmed cell death. While traditional cancer research has focused on why cancer cells seemingly proliferate in an uncontrollable fashion, new research has determined that the problem with cancer cells may instead be that the natural internal maturation pathways common to normal cells are in someway suppressed in cancerous cells. Therefore, cancer cells are able to survive longer than normal cells. Based on these new findings, the identification and development of new compounds which will selectively stimulate apoptosis offers a significant new approach to combating cancer.

Ohio State researchers have isolated compounds useful for inducing apoptosis in proliferative cells, including but not limited to cancer cells. The compounds are further useful for treating, inhibiting, and delaying the onset of cancer in mammals, and especially in humans. Cancers that these compounds work particularly well against include leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, bladder cancer, lymphoma, and breast cancer. Surprisingly, the compounds of the present invention are able to induce apoptosis in cancer cells independent of the level of Bcl-2 expression and p53 functional status, which means that the inventive compounds are potent even against cancers that are androgen-independent, such as hormone-refractory prostate cancer.

Potential Applications:

Treatment of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, bladder cancer, lymphoma, and breast cancer.

Advantages:

Can treat cancer cells that are androgen-independent or are resistant to current treatment.

Treatment of Inflammation with Latency Associated Peptide

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Summary:

Researchers at The Ohio State University have developed new methods for treatment of inflammation associated with pulmonary diseases. Pulmonary inflammation can lead to the development of excess fibrotic material which impairs function of the lung with severe health consequences. Conventional treatment for inflammation involves anti-inflammatory therapies that have limited efficacy and serious side effects. The method for treatment of inflammation developed at Ohio State involves use of latency-associated peptide (LAP). LAP is transcribed from the same gene as TGF-beta. In addition to its binding to TGF-beta to form an inactive complex LAP has been found to interfere with fibrosis by a mechanism independent of binding to TGF-beta. By controlling fibrosis associated with inflammation in pulmonary diseases patients may have a significantly better outcome.

Potential Applications:

• Pulmonary Inflammation and Fibrosis • Fibrotic disease in other tissue types

Engineered Chondrocytes as Xenograft Transplants

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Summary:

A novel regenerative strategy for tissue repair has been developed that reduces and/or eliminates the drawbacks associated with current treatments for injured or inferior tissues. The use of xenogeneic cell sources in these regenerative strategies is one approach. The strategy also provides a transplant system including a cell adapted for transplant from a xenogeneic donor to a host, wherein the cell is engineered to express pdl1. Regenerative strategies for bone and cartilage repair offer significant impact by reducing morbidity of musculoskeletal diseases and their burden on the socioeconomic system, as well as reducing costs for reimbursements by the present health care system.

Potential Applications:

  • Companies that provide therapies for patients with musculoskeletal afflictions

Advantages:

  • Highly effective therapy at lower cost.
  • Reduces cost of patient hospitalization, dependent living, lost work and morbidity that limit quality of life.
  • Does not trigger immune response in the host.

New Psoralen Sensitizers for Viral Inactivation. Triplet State Quenchers as side chains

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Summary:

Researchers at OSU have modified the basic structure of psoralens such that the viral inactivation function is preserved while mutagenic breakdown products and undesirable reactions have been eliminated. Treatment with psoralens in the presence of UV light can inactivate viruses, thus, psoralens offer an attractive chemical to inactivate viruses, such as HIV. However, these reactions can also cause damage to desired components in platelet concentrates. In addition, breakdown products of the psoralens can be mutagenic. These psoralen analogues are water soluble and are useful for inactivating viruses and other microbial contaminants in peripheral blood cells, allogenic transplants, collected whole blood, media used in the preparation of anti-viral vaccines, cell culture media and xenotransplants.

Potential Applications:

Treatment of individuals with viral infections, microbial contaminant or patients that have undergone a transplant.

Advantages:

Use of psoralens that have proven effective without the harmful side effects from breakdown products or mutagenesis.

Supercritical Carbon Dioxide Method for Embedding High Molecular Weight Biomolecules in Synthetic Polymers

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Summary:

This procedure uses supercritical carbon dioxide to impregnate proteins and other biologically active molecules into a polymethylmethacrylate (PMMA) matrix suitable for tissue engineering and transplant into humans. These materials would achieve greater biocompatibility in physiological enviroments. The exposure to the supercritical carbon dioxide provides simultaneous sterilization and opportunities for the production of foamed morphologies similar to those found in both hard and soft tissues in vivo. This combination of enhanced diffusion, foaming and sterilization can conceivably be exploited to produce or modify a variety of biomedical materials.

Potential Applications:

  • Biomedical implants
  • Cancer treatment

Advantages:

  • Enhanced diffusion
  • Sterilization
  • Function selectivity
  • Low costs

Novel Peptide Vaccines and Active Immunization for Cancer Prevention and Therapy

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Summary:

Researchers at The Ohio State University have developed an active prophylactic/preventive human cancer vaccine for HER-2 expressing cancers. HER-2/neu is a unique oncoprotein that is over-expressed in a number of human tumors including breast, ovary, lung, stomach, endometrium and bladder, and is associated with markedly aggressive forms of cancer with a worse prognosis of several malignancies. Existing passive immunotherapeutic approaches require frequent treatments, have limited duration of action, produce undesired immunogenecity and incur significant risks of cardiotoxicities. The OSU technology may overcome many of these concerns by allowing the patient to produce their own antibodies to HER-2. The novel vaccine is now nearing completion of Phase I human clinical trials at OSU’s James Cancer Hospital. Results from advanced cancer patients (Stage IV) show no toxicity and several patients have had high immune responses to the vaccine. The peptide design platform on which this vaccine is based is highly extendable into therapeutics and other diseases:

  • Inhibiting tumor growth, invasion and metastasis: the inclusion of a VEGF inhibitor, a known contributor to angiogenesis, to the HER-2 vaccine can improve cancer treatment (status: preclinical evaluation).
  • Developing additional vaccines: the development of a novel vaccine for the treatment and prevention of epithelial ovarian cancer is underway (status: preclinical studies).
  • Identifying new approaches for disease treatment: new peptide therapeutics for autoimmune diseases can treat multiple sclerosis, rheumatoid arthritis, diabetes, lupus and allergies (status: preclinical testing).

The investment to date is:

  • HER-2/VEGF $4.5 million, $1.2 million pending
  • Autoimmune $600K

Currently, for the Cancer Vaccine and Therapeutics there are four patent families in prosecution and one US patent allowed. A US patent is pending for the autoimmune application.

Potential Applications:

Treatment and prevention of breast, ovarian, lung, stomach, endometrial and bladder cancers.

Advantages:

  • The patient produces the antibodies, reducing the amount and frequency of dosing
  • Significantly lower probability of toxicity compared to existing treatments.
  • Active immunization approach allows a patient to be treated before cancer is detected.