The Use of Informer Sets in Screening: Perspectives on an Efficient Strategy to Identify New Probes

Clemons, Paul A.; Bittker, Joshua A.; Wagner, Florence F.; Hands, Allison; Dančík, Vlado; Schreiber, Stuart L.; Choudhary, Amit; Wagner, Bridget K.

doi:10.1177/24725552211019410

Cited by 8 publications

(8 citation statements)

References 46 publications

(53 reference statements)

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“…We selected four chemical libraries (20,876 total compounds) for screening. First, the DOS Informer Set is a subset of the Broad Institute DOS library, , containing 9510 compounds (192 hits2.02% hit rate) representing ∼30 diverse structural families. Second, the DOS-A library (3840 compounds, 29 hits0.76% hit rate) is a collection of DOS compounds selected for performance diversity based on a combination of gene expression analysis and cell painting .…”

Section: Results and Discussionmentioning

confidence: 99%

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity

et al. 2022

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Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.

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Section: Results and Discussionmentioning

confidence: 99%

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity

et al. 2022

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“…While physical copies of the compound set are not a shared resource, the data within CTRP is immensely useful to the cancer‐focused research community and once again demonstrates the impact of open sharing. 23 …”

Section: Introductionmentioning

confidence: 99%

“…While physical copies of the compound set are not a shared resource, the data within CTRP is immensely useful to the cancer-focused research community and once again demonstrates the impact of open sharing. 23 A key deliverable of TREAT-AD is small molecule tools that enable characterization of the AD targets nominated by AMP AD investigators. While some of these targets are generally underexplored, others are new to AD and thus research results outside of the context of AD have been published.…”

Section: Introductionmentioning

confidence: 99%

“…The Informer Set, which is a living resource, has since been expanded to include ≈545 molecules and corresponding data deposited in CTRP. While physical copies of the compound set are not a shared resource, the data within CTRP is immensely useful to the cancer‐focused research community and once again demonstrates the impact of open sharing 23 …”

Section: Introductionmentioning

confidence: 99%

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AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery

Potjewyd

Annor-Gyamfi

Aubé

et al. 2022

A&D Transl Res & Clin Interv

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Introduction The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP AD) program. Methods Publicly available resources, such as literature and databases, enabled a data‐driven effort to identify existing small molecule modulators for many protein products expressed by the genes nominated by AMP AD and suitable positive control compounds to be included in the set. Compounds contained within the set were manually selected and annotated with associated published, predicted, and/or experimental data. Results We built an annotated set of 171 small molecule modulators targeting 98 unique proteins that have been nominated by AMP AD consortium members as novel targets for the treatment of AD. The majority of compounds included in the set are inhibitors. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which will require further optimization. A physical copy of the AD Informer Set can be requested on the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) website. Discussion Small molecules that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD.

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“…5,6 More recently, these sets have been assembled with a therapeutic area focus, such as oncology. 7,8 A well-designed chemogenomic set includes compounds that cover expansive pharmacological space. These can include Food and Drug Administration-approved drugs as well as agents in clinical trials to provide opportunities for the repurposing of advanced candidates.…”

Section: Introductionmentioning

confidence: 99%

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

Potjewyd

Annor-Gyamfi

Aubé

et al. 2022

A&D Transl Res & Clin Interv

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Introduction A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data-tools/ad-informer-set/. Methods Small subsets of AD Informer Set compounds were selected for AD‐relevant profiling. Nine compounds targeting proteins expressed by six AD‐implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT‐AD) teams were selected for G‐protein coupled receptor (GPCR), amyloid beta (Aβ) and tau, and pharmacokinetic (PK) studies. Four non‐overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)‐derived neurons were treated with the same nine compounds and secretion of Aβ peptides (Aβ40 and Aβ42) as well as levels of phosphophorylated tau (p‐tau, Thr231) and total tau (t‐tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain‐specific penetrance values for these compounds. As a final cell‐based study, a non‐overlapping subset of four compounds was selected based on single‐concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p‐tau, Aβ40, and/or Aβ42 and blood–brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single‐concentration phagocytosis results were validated as predictive of dose–response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds.

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The Use of Informer Sets in Screening: Perspectives on an Efficient Strategy to Identify New Probes

Cited by 8 publications

References 46 publications

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity

AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology

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