RESUMO
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Acetilação , Animais , Glicemia/metabolismo , Células Cultivadas , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Resistência à Insulina , Camundongos , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.
Assuntos
Descoberta de Drogas , Bibliotecas de Moléculas Pequenas , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMO
The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene ß-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.
Assuntos
Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Neoplasias/genéticaRESUMO
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Evolução Molecular , Variação Genética/genética , Instabilidade Genômica/genética , Transcrição Gênica/genética , Neoplasias da Mama/patologia , Proliferação de Células , Forma Celular , Células Clonais/citologia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Variação Genética/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Humanos , Células MCF-7 , Reprodutibilidade dos TestesRESUMO
Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Azetidinas/uso terapêutico , Descoberta de Drogas , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Azetidinas/farmacologia , Citosol/enzimologia , Modelos Animais de Doenças , Feminino , Fígado/efeitos dos fármacos , Fígado/parasitologia , Macaca mulatta/parasitologia , Malária Falciparum/prevenção & controle , Malária Falciparum/transmissão , Masculino , Camundongos , Fenilalanina-tRNA Ligase/antagonistas & inibidores , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Plasmodium falciparum/citologia , Plasmodium falciparum/enzimologia , SegurançaRESUMO
Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules. We developed a multiplexed bead-based technology to screen compounds for disruption of the CARD9-TRIM62 interaction. We identified compounds that directly and selectively bind CARD9, disrupt TRIM62 recruitment, inhibit TRIM62-mediated ubiquitinylation of CARD9, and demonstrate cellular activity and selectivity in CARD9-dependent pathways. Taken together, small molecules targeting CARD9 illustrate a path toward improved IBD therapeutics.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/genética , Ensaio de Imunoadsorção Enzimática/métodos , Variação Genética , Doenças Inflamatórias Intestinais/genética , Avaliação Pré-Clínica de Medicamentos , Marcadores Genéticos , Ensaios de Triagem em Larga Escala , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ligação Proteica , Sensibilidade e Especificidade , Proteínas com Motivo Tripartido/antagonistas & inibidores , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genéticaRESUMO
Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with â¼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Aflatoxinas/química , Aflatoxinas/farmacologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Simulação por Computador , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Estrutura Molecular , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo RealRESUMO
High-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , HumanosRESUMO
Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Leucemia , Células-Tronco Neoplásicas/efeitos dos fármacos , Linhagem Celular Tumoral , Células-Tronco Hematopoéticas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/fisiologiaRESUMO
Integration of flexible data-analysis tools with cheminformatics methods is a prerequisite for successful identification and validation of "hits" in high-throughput screening (HTS) campaigns. We have designed, developed, and implemented a suite of robust yet flexible cheminformatics tools to support HTS activities at the Broad Institute, three of which are described herein. The "hit-calling" tool allows a researcher to set a hit threshold that can be varied during downstream analysis. The results from the hit-calling exercise are reported to a database for record keeping and further data analysis. The "cherry-picking" tool enables creation of an optimized list of hits for confirmatory and follow-up assays from an HTS hit list. This tool allows filtering by computed chemical property and by substructure. In addition, similarity searches can be performed on hits of interest and sets of related compounds can be selected. The third tool, an "S/SAR viewer," has been designed specifically for the Broad Institute's diversity-oriented synthesis (DOS) collection. The compounds in this collection are rich in chiral centers and the full complement of all possible stereoisomers of a given compound are present in the collection. The S/SAR viewer allows rapid identification of both structure/activity relationships and stereo-structure/activity relationships present in HTS data from the DOS collection. Together, these tools enable the prioritization and analysis of hits from diverse compound collections, and enable informed decisions for follow-up biology and chemistry efforts.
Assuntos
Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Relação Estrutura-Atividade , Algoritmos , Técnicas de Química Combinatória , Bases de Dados Factuais , HumanosRESUMO
High-content screening for small-molecule inducers of insulin expression identified the compound BRD7389, which caused alpha-cells to adopt several morphological and gene expression features of a beta-cell state. Assay-performance profile analysis suggests kinase inhibition as a mechanism of action, and we show that biochemical and cellular inhibition of the RSK kinase family by BRD7389 is likely related to its ability induce a beta-cell-like state. BRD7389 also increases the endocrine cell content and function of donor human pancreatic islets in culture.
Assuntos
Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/metabolismo , Insulina/biossíntese , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica/efeitos dos fármacos , Células Secretoras de Glucagon/citologia , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolonas/química , Interferência de RNA , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/genética , Técnicas de Cultura de TecidosRESUMO
The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.
RESUMO
MOTIVATION: In high-throughput screens (HTS) of small molecules for activity in an in vitro assay, it is common to search for active scaffolds, with at least one example successfully confirmed as an active. The number of active scaffolds better reflects the success of the screen than the number of active molecules. Many existing algorithms for deciding which hits should be sent for confirmatory testing neglect this concern. RESULTS: We derived a new extension of a recently proposed economic framework, diversity-oriented prioritization (DOP), that aims-by changing which hits are sent for confirmatory testing-to maximize the number of scaffolds with at least one confirmed active. In both retrospective and prospective experiments, DOP accurately predicted the number of scaffold discoveries in a batch of confirmatory experiments, improved the rate of scaffold discovery by 8-17%, and was surprisingly robust to the size of the confirmatory test batches. As an extension of our previously reported economic framework, DOP can be used to decide the optimal number of hits to send for confirmatory testing by iteratively computing the cost of discovering an additional scaffold, the marginal cost of discovery. CONTACT: swamidass@wustl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Ensaios de Triagem em Larga Escala , Algoritmos , Análise por ConglomeradosRESUMO
Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.
Assuntos
Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ratos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways.
Assuntos
Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Indóis/química , Indóis/farmacologia , Transdução de SinaisRESUMO
Most methods of deciding which hits from a screen to send for confirmatory testing assume that all confirmed actives are equally valuable and aim only to maximize the number of confirmed hits. In contrast, "utility-aware" methods are informed by models of screeners' preferences and can increase the rate at which the useful information is discovered. Clique-oriented prioritization (COP) extends a recently proposed economic framework and aims--by changing which hits are sent for confirmatory testing--to maximize the number of scaffolds with at least two confirmed active examples. In both retrospective and prospective experiments, COP enables accurate predictions of the number of clique discoveries in a batch of confirmatory experiments and improves the rate of clique discovery by more than 3-fold. In contrast, other similarity-based methods like ontology-based pattern identification (OPI) and local hit-rate analysis (LHR) reduce the rate of scaffold discovery by about half. The utility-aware algorithm used to implement COP is general enough to implement several other important models of screener preferences.
Assuntos
Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Descoberta de Drogas/métodos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Algoritmos , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/química , Proteínas Cromossômicas não Histona/química , Ensaios de Triagem em Larga Escala , Humanos , Histona Desmetilases com o Domínio Jumonji/química , Modelos Moleculares , Bibliotecas de Moléculas PequenasRESUMO
We report the outcome of a high-throughput small-molecule screen to identify novel, nontoxic, inhibitors of Trypansoma cruzi, as potential starting points for therapeutics to treat for both the acute and chronic stages of Chagas disease. Two compounds were identified that displayed nanomolar inhibition of T. cruzi and an absence of activity against host cells at the highest tested dose. These compounds have been registered with NIH Molecular Libraries Program (probes ML157 and ML158).
Assuntos
Bibliotecas de Moléculas Pequenas , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Concentração Inibidora 50 , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/químicaRESUMO
The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.
Assuntos
Antifúngicos/farmacologia , Inibidores de Calcineurina , Candida albicans/efeitos dos fármacos , Fluconazol/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinolinas/farmacologia , Antifúngicos/química , Calcineurina/metabolismo , Candida albicans/crescimento & desenvolvimento , Candida albicans/isolamento & purificação , Relação Dose-Resposta a Droga , Fluconazol/química , Proteínas de Choque Térmico HSP90/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Small-molecule discovery typically involves large-scale screening campaigns, spanning multiple compound collections. However, such activities can be cost- or time-prohibitive, especially when using complex assay systems, limiting the number of compounds tested. Further, low hit rates can make the process inefficient. Sparse coverage of chemical structure or biological activity space can lead to limited success in a primary screen and represents a missed opportunity by virtue of selecting the "wrong" compounds to test. Thus, the choice of screening collections becomes of paramount importance. In this perspective, we discuss the utility of generating "informer sets" for small-molecule discovery, and how this strategy can be leveraged to prioritize probe candidates. While many researchers may assume that informer sets are focused on particular targets (e.g., kinases) or processes (e.g., autophagy), efforts to assemble informer sets based on historical bioactivity or successful human exposure (e.g., repurposing collections) have shown promise as well. Another method for generating informer sets is based on chemical structure, particularly when the compounds have unknown activities and targets. We describe our efforts to screen an informer set representing a collection of 100,000 small molecules synthesized through diversity-oriented synthesis (DOS). This process enables researchers to identify activity early and more extensively screen only a few chemical scaffolds, rather than the entire collection. This elegant and economic outcome is a goal of the informer set approach. Here, we aim not only to shed light on this process, but also to promote the use of informer sets more widely in small-molecule discovery projects.
Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas , Humanos , Relação Estrutura-AtividadeRESUMO
Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.