Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target

Waters, Nigel J.; Daigle, Scott R.; Rehlaender, Bruce N.; Basavapathruni, Aravind; Campbell, Carly; Jensen, Tyler B.; Truitt, Brett F.; Olhava, Edward J.; Pollock, Roy M.; Stickland, Kim; Dovletoglou, Angelos

doi:10.1016/j.jconrel.2015.09.023

Cited by 25 publications

(22 citation statements)

References 22 publications

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“…[19][20][21][22][23] Pinometostat is a potent and selective small-molecule DOT1L inhibitor with subnanomolar affinity for DOT1L and .37 000-fold selectivity against other histone methyltransferases. [23][24][25][26] Pinometostat selectively inhibits intracellular H3K79 methylation in a concentration-and time-dependent manner. In cells harboring the MLL translocation, inhibition of H3K79 methylation results in concentration-and time-dependent inhibition of downstream gene expression and consequent cell killing, with half-maximal inhibitory concentration values for cell growth in the ,1 mM range.…”

Section: Introductionmentioning

confidence: 99%

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Stein

Garcia‐Manero

Rizzieri

et al. 2018

Blood

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347

281

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Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia () gene rearrangements () resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.

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Section: Introductionmentioning

confidence: 99%

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Stein

Garcia‐Manero

Rizzieri

et al. 2018

Blood

Self Cite

347

281

View full text Add to dashboard Cite

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“…In MLL‐r leukemia, DOT1L recruitment to MLL target genes, such as the HoxA cluster, leads to aberrant H3K79 methylation and increased transcription (reviewed in Vlaming & Van Leeuwen, ). Although the DOT1L inhibitor Pinometostat (EPZ‐5676) has shown promising results in the laboratory and is currently in clinical development (Bernt et al , ; Daigle et al , ; Waters et al , ; Stein & Tallman, ; Stein et al , ), the cellular mechanisms and consequences of DOT1L deregulation are only just being uncovered (Vlaming & Van Leeuwen, ).…”

Section: Introductionmentioning

confidence: 99%

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L‐dose dependency in HDAC1‐deficient thymic lymphoma

et al. 2019

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DOT 1L methylates histone H3K79 and is aberrantly regulated in MLL ‐rearranged leukemia. Inhibitors have been developed to target DOT 1L activity in leukemia, but cellular mechanisms that regulate DOT 1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC 1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT 1L dosage. Furthermore, cell lines derived from Hdac1 Δ/Δ thymic lymphomas were sensitive to a DOT 1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC 1 and DOT 1L with impact in murine thymic lymphoma development.

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“…The metabolic instability further prevents the application of the conventional dosing method including intraperitoneal injection and oral administration. Hence, in preclinical and clinical trials, rats and leukemia patients were administrated with EPZ-5676 by continuous Intravenous (IV) infusion for a long dosing time (about 10 -28 days) at a relative high dosage to present anti-leukemic function [31][32][33]. Considering the monotonous structural type, the poor pharmacokinetics and the defective dosing method of adenosine-containing inhibitors, there is an urgent need for discovering novel DOT1L inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

Luo

Wang

Zou

et al. 2016

Journal of Molecular Graphics and Modelling

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Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target

Cited by 25 publications

References 22 publications

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L‐dose dependency in HDAC1‐deficient thymic lymphoma

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

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