Genomic approaches to small molecule discovery

Stegmaier, Kimberly

doi:10.1038/leu.2009.29

Cited by 5 publications

(2 citation statements)

References 69 publications

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“…In light of these results, we prioritized TDZ2 and TDZ6 for in vivo testing. We evaluated neuroleptic effects by a stepped-dose test 29 in NSG mice treated with increasing doses of drug (1,5,8,10,12, and 15 mg/kg), and found that both the analogues TDZ2 and TDZ6 did not provoke akinesia, either at the dose where TDZ was efficient (at least 8 mg/kg), or at higher doses (n 5 3; Figure 6D). We finally selected TDZ6 as the analogue with the efficacy to prevent AML progression in vivo and found that it counteracted tumor growth at a dosage equivalent to TDZ, 8 mg/kg (n 5 5; Figure 6E), with the great possibility of potentiating the standard chemotherapy effect.…”

Section: Tdz Targets Mll-af6-aml Cytoskeleton Dynamicsmentioning

confidence: 99%

“…9,10 High-throughput drug screening (HTDS) approaches are currently used to test whether novel compounds or drugs known to be active in other malignancies may be effective in acute leukemia, with the goal of introducing them rapidly into pediatric clinical trials. 7,11,12 We considered this strategy to prioritize the identification of drugs with therapeutic benefits against the childhood AML variant harboring the t(6;11)(q27;q23) chromosomal rearrangement, which defines a peculiar biological and clinical subset of AML, where the genes lysine methyltransferase 2A (KMT2A, MLL) and afadin (AFDN, AF6) are fused, generating the chimeric protein MLL-AF6. 13,14 We and other international groups previously identified MLL-AF6-rearranged AML as the most aggressive among the pediatric AMLs with MLL rearrangements, with a low probability of event-free survival, reported to range from 11% to 23% at 5 years.…”

Section: Introductionmentioning

confidence: 99%

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Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death

et al. 2020

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In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug’s safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials.

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Section: Tdz Targets Mll-af6-aml Cytoskeleton Dynamicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death

et al. 2020

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Could Be Systems-Directed Therapy Approaches Promising in Glioblastoma Patients?

Grauer

Hau

2010

From Molecular to Modular Tumor Therapy

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Incorporating Zebrafish Omics into Chemical Biology and Toxicology

Sukardi

Ung²,

Gong³

et al. 2010

Zebrafish

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In this communication, we describe the general aspects of omics approaches for analyses of transcriptome, proteome, and metabolome, and how they can be strategically incorporated into chemical screening and perturbation studies using the zebrafish system. Pharmacological efficacy and selectivity of chemicals can be evaluated based on chemical-induced phenotypic effects; however, phenotypic observation has limitations in identifying mechanistic action of chemicals. We suggest adapting gene-expression-based high-throughput screening as a complementary strategy to zebrafish-phenotype-based screening for mechanistic insights about the mode of action and toxicity of a chemical, large-scale predictive applications and comparative analysis of chemical-induced omics signatures, which are useful to identify conserved biological responses, signaling pathways, and biomarkers. The potential mechanistic, predictive, and comparative applications of omics approaches can be implemented in the zebrafish system. Examples of these using the omics approaches in zebrafish, including data of ours and others, are presented and discussed. Omics also facilitates the translatability of zebrafish studies across species through comparison of conserved chemical-induced responses. This review is intended to update interested readers with the current omics approaches that have been applied in chemical studies on zebrafish and their potential in enhancing discovery in chemical biology.

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Genomic approaches to small molecule discovery

Cited by 5 publications

References 69 publications

Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death

Thioridazine requires calcium influx to induce MLL-AF6–rearranged AML cell death

Could Be Systems-Directed Therapy Approaches Promising in Glioblastoma Patients?

Incorporating Zebrafish Omics into Chemical Biology and Toxicology

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