Proteostasis Consortium

The Goal

One goal of the Proteostasis Pharmacology Subgroup is to coordinate the development of 96- and 384-well microplate libraries that are composed of molecules with activity against proteins and pathways in the Proteostasis Network. We envision that these plates could be used across the Proteostasis Consortium and beyond to ask important questions about which targets and pathways are most important in disease models. An important advantage of that strategy is that the same compounds would be used across many different biochemical, cell-based and animal models, building a broad knowledge-based. The use of such chemical libraries might also reveal new relationships between Proteostasis Network and disease, as well as minimize use of poorly characterized compounds.

The Proteostasis Regulator Team

During the past two years, the Proteostasis Consortium team, including members of the Finkbeiner (University of California San Francisco and Gladstone Institute), Finley (Harvard Medical School), Frydman (Stanford), Gestwicki (UCSF), Kelly (Scripps Research), and Morimoto (Northwestern University) laboratories have been working together to review potential molecules for inclusion in the Proteostasis Regulator libraries. This work has also been conducted with expert assistance from collaborators in academics and industry. We hope that this project also receives ongoing guidance from the community.

Methods and Background

Our first goal is to create an up-to-date list of publicly available small molecule Proteostasis Regulators. To achieve this goal, we first assembled a large set of potential compounds, followed by a literature review to triage molecules that do not yet have sufficient evidence of target engagement, metabolism or permeability. In deciding which compounds were suitable for given targets, we also considered criteria such as availability of closely related negative controls and knowledge of in vitro and in vivo pharmacology. Even more restrictive criteria define a subset of these compounds (see the Chemical Probes Annotation). In cases where multiple compounds against the same target were considered suitable, we also imposed restrictions on the total number to be included, with the goal of keeping the initial library concise.

Using this approach, we have created a draft set of Proteostasis Regulators, focusing on molecules that target: protein synthesis, quality control, folding, trafficking and degradation pathways, along with stress response targets. Key literature evidence for each compound is included. As a next step, we will build physical versions of this library and characterize the compounds for purity and stability. Once established, these plates will be made available to the proteostasis research community at-large for testing. Ultimately, we will integrate data across these experiments using a web-based tool. We anticipate that this tool will facilitate cross-validation across publicly available databases containing genomic, transcriptomic, proteomic, phenotypic and functional information.

Current Plate Maps