Dataset Information

Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.

ABSTRACT: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3? (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT.A subset of over 16,000 inhibitors of HsGSK-3 ? from the Pfizer compound collection was screened against the shorter of two orthologues of TbruGSK-3. The resulting active compounds were tested for selectivity versus HsGSK-3? and a panel of human kinases, as well as in vitro anti-trypanosomal activity. Structural analysis of the human and trypanosomal enzymes was also performed.We identified potent and selective compounds representing potential attractive starting points for a drug discovery program. Structural analysis of the human and trypanosomal enzymes also revealed hypotheses for further improving selectivity of the compounds.

SUBMITTER: Oduor RO

PROVIDER: S-EPMC3071371 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.

Oduor Richard O RO Ojo Kayode K KK Williams Gareth P GP Bertelli Francois F Mills James J Maes Louis L Pryde David C DC Parkinson Tanya T Van Voorhis Wesley C WC Holler Tod P TP

PLoS neglected tropical diseases 20110405 4

<h4>Background</h4>Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partner ...[more]

PMID: 21483717

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Project description:BACKGROUND:Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides the source of pathologic light chains, and the resulting organ dysfunction caused by deposition of amyloid light chain fibrils. There are no FDA approved treatments for AL amyloidosis; regimens developed for multiple myeloma are used off-label to treat the plasma cell disorder and no therapies are directed at organ deposition. Thus, an unmet medical need persists despite advances in disease management. A public-private partnership was recently formed between the Amyloidosis Research Consortium (ARC) and the US Food and Drug Administration (FDA) to bridge scientific gaps in drug development for the treatment of AL amyloidosis. MAIN BODY:The inaugural Amyloidosis Forum was convened at FDA on 12 November 2019 and led by a multidisciplinary panel of physicians, health outcomes professionals, and representatives from the FDA, ARC, and pharmaceutical companies. Patients provided important perspectives on the pathway to diagnosis, challenges of rigorous treatment, and the burden of disease. The panel reviewed the epidemiology, pathobiology, and clinical features of AL amyloidosis. Hematologic characteristics, staging systems, and response criteria were examined with clear consensus that a "deep response" to plasma cell-directed treatments was critical to overall survival. Emphasis was placed on the heterogeneous clinical phenotypes of AL amyloidosis, including cardiovascular, renal, neurological, and gastrointestinal system manifestations that contribute to morbidity and/or mortality, but render challenges to clinical trial endpoint selection. FDA representatives discussed regulatory perspectives regarding demonstration of clinical benefits of investigational therapies in the context of a rare disease with multi-systemic manifestations. The panel also highlighted the potential importance of well-designed health-related quality of life instruments, quantification of system organ effects, the potential of advanced imaging technologies, and survival prediction models. CONCLUSIONS:The Amyloidosis Forum identified a clear need for novel trial designs that are scientifically rigorous, feasible, and incorporate clinically meaningful endpoints based on an understanding of the natural history of the disease in an evolving therapeutic landscape. Future forums will delve into these issues and seek to include participation from additional stakeholders.

Dataset Information

Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.

Publications

Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.

Similar Datasets

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