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Blue Bell, PA, United States

Patent
Locus Pharmaceuticals | Date: 2010-04-28

A compound of formula (I): wherein all symbols have the same meanings as defined in the specification; a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, has a Btk inhibitory activity, and is useful as a method for preventing and/or treating a rheumatoid arthritis, an autoimmune disease, a B cell lymphoma of cancer, and the like.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 180.22K | Year: 2004

DESCRIPTION (provided by applicant): Medical Need: Human immunodeficiency virus (HIV), the etiologic agent of acquired immune-deficiency syndrome (AIDS), continues to infect millions of people worldwide. Despite recent improvements in antiretroviral thera


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2004

DESCRIPTION (provided by applicant): Medical Need: Human immunodeficiency virus (HIV), the etiologic agent of acquired immune-deficiency syndrome (AIDS), continues to infect millions of people worldwide. Despite recent improvements in anti-retroviral th


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 298.90K | Year: 2007

DESCRIPTION (provided by applicant): Despite recent advances in cancer treatment, the identification of novel anti-cancer therapeutic agents remains a pressing need. Heat Shock Protein 90 (Hsp90) is a molecular chaperone which binds to and folds several client proteins including a number of key cancer-relevant targets such as the kinases Bcr-Abl, Raf-1, and SRC family kinases such as SRC, LCK and FYN, mutated p53, ErbB2, and the steroid hormone receptors. Disruption of the folding process by Hsp90 inhibition leads to degradation of these client proteins. Because Hsp90 client proteins are so important in processes critical to the growth and survival of cancer cells (e.g., signal transduction and in transcription), Hsp90 inhibitors may serve as effective chemotherapeutic agents against a number of cancers. This hypothesis has been clinically validated by the geldanamycin analogs 17- AAG, and 17-DMAG. However, these ansamycin analogs suffer from poor pharmacokinetic properties and off- target toxicity. Thus, there is a need for improved Hsp90 inhibitors. This Phase I proposal focuses on synthesis, biological assessment and crystallography of four novel series of Hsp90 inhibitors that were designed using Locus' innovative computational technology. The ultimate proposed product of this research is an orally administered cancer therapeutic drug targeting Hsp90.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 926.11K | Year: 2005

DESCRIPTION (provided by applicant): Medical Need: Human immunodeficiency virus (HIV), the etiologic agent of acquired immune-deficiency syndrome (AIDS), continues to infect millions of people worldwide. Despite recent improvements in patient outcomes resulting from highly active antiretroviral therapy (HAART), there remains an urgent need for novel and improved methods of treatment for individuals living with AIDS. This need arises from limitations of existing treatment options, such as emergence of resistant viruses and adverse side effects. Viral entry into the host cell proceeds via formation of a gp41 six-helical coiled coil, which is the final step of HIV-1 membrane fusion and infection of the host cell. Due to the need for additional therapeutic modalities that are safe and well tolerated, inhibition of HIV-1 gp41 function is an innovative new treatment modality. Enfuvirtide (Fuzeon) is a safe and effective peptide inhibitor of gp41 function recently approved by the FDA for treating HIV-1 infection. However, manufacturing, cost and dosing difficulties limit the use of Fuzeon to a small portion of the HIV-1 infected population. A small molecule drug acting on HIV-1 gp41 that could be administered by oral dosing would constitute a significant advancement in the treatment of AIDS. Goal of Research: Using its innovative computational methodology, Locus Pharmaceuticals identified two chemical classes of small molecule HIV gp41 inhibitory compounds. Further improvement of these molecules as drug candidates requires the input of co-crystal structures as a basis for computational design. With the aid of a Phase I SBIR grant, Locus demonstrated the feasibility of generating such co-crystal structures. The focus of this proposal is to solve co-crystal structures of the compounds in complex with gp41 in order to enable computational and structure-based design. These structures will then be used as input for further computational design and optimization of gp41 inhibitory small molecules. The ultimate goal of this research is the identification of drug candidate small molecule gp41 inhibitory compounds for the treatment of AIDS caused by HIV-1 infection. Specific Aims: Obtain a co-crystal structure of a functionally relevant HIV-1 gp41 HR-1 domain in complex with a bound small molecule compound that inhibits gp41 function. Using these new co-crystal structures, apply computational and structure-based methods to design then chemical synthesis to generate additional small molecule gp41 inhibitors with improved potency.

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