JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA processing

Kakegawa, Junya; Sakane, Naoki; Suzuki, Kensuke; Yoshida, Takayuki

doi:10.1016/j.bbrc.2019.08.004

Cited by 33 publications

(35 citation statements)

References 26 publications

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Section: Plos Onementioning

confidence: 99%

“…TO-207 formerly known as JTE-607, an N-benzoyl-L-phenylalanine derivative compound, is a novel inhibitor of multiple cytokines [18]. TO-207 is thought to inhibit cytokine production by antagonizing mRNA 3'-end processing and maturation [18]. 3'-End processing requires multi-subunit complexes, including the cleavage and polyadenylation specificity factor (CPSF), cleavage stimulation factor (CstF), cleavage factor I, cleavage factor II, poly(A) polymerase, and scaffold proteins such as symplekin [21,22].…”

Section: Plos Onementioning

confidence: 99%

“…endonucleolytic cleavage about 21 nucleotides downstream of the poly(A) signal. Kakegawa et al [18] showed that TO-207/JTE-607 exerts its effect by binding directly to CPSF3. LPSstimulated monocytes upregulated the transcription of IL-8 mRNA, but the addition of TO-207 significantly inhibited the maturation of IL-8 pre-mRNA, resulting in a reduction of the IL-8 protein level.…”

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We previously demonstrated that the investigational drug TO-207, formerly known as JTE-607, preferentially inhibits abnormal activation of macrophages without attenuating T-cell function [15][16][17][18]. TO-207 is an mRNA 3'-end processing antagonist that can inhibit the secretion of multiple cytokines [18]. Additionally, TO-207 treatment inhibited the in vitro production of IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-1Rα, and GM-CSF in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells [15].…”

Section: Introductionmentioning

confidence: 99%

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The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

Futami

Suzuki²,

Kato

et al. 2020

PLoS ONE

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Cancer immunotherapy using chimeric antigen receptor-armed T (CAR T) cells have been shown to improve outcomes significantly in patients with hematological malignancies. However, cytokine release syndrome (CRS) remains a risk. CRS is characterized by the excessive activation of CAR T cells and macrophages. Signs and symptoms of CRS are usually resolved after steroid administration, but steroids abrogate the expansion and persistence of CAR T cell populations. Tocilizumab is a humanized monoclonal antibody (mAb) that attenuates CRS without significant loss of CAR T cell activity. However, interleukin-6 (IL-6)/ IL-6 receptor (IL-6R) blockade alone cannot relieve CRS symptoms fully, and novel treatments are needed to prevent or cure CRS. TO-207 is an N-benzoyl-L-phenylalanine derivative that significantly inhibits inflammatory cytokine production in human monocyte and macrophage-specific manner. We investigated whether TO-207 could inhibit cytokine production without impairing CAR T cell function in a CRS-simulating co-culture system.

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Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

Futami

Suzuki²,

Kato

et al. 2020

PLoS ONE

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Computing Metal‐Binding Proteins for Therapeutic Benefit

et al. 2021

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Over one third of biomolecules rely on metal ions to exert their cellular functions. Metal ions can play a structural role by stabilizing the structure of biomolecules, a functional role by promoting a wide variety of biochemical reactions, and a regulatory role by acting as messengers upon binding to proteins regulating cellular metal‐homeostasis. These diverse roles in biology ascribe critical implications to metal‐binding proteins in the onset of many diseases. Hence, it is of utmost importance to exhaustively unlock the different mechanistic facets of metal‐binding proteins and to harness this knowledge to rationally devise novel therapeutic strategies to prevent or cure pathological states associated with metal‐dependent cellular dysfunctions. In this compendium, we illustrate how the use of a computational arsenal based on docking, classical, and quantum‐classical molecular dynamics simulations can contribute to extricate the minutiae of the catalytic, transport, and inhibition mechanisms of metal‐binding proteins at the atomic level. This knowledge represents a fertile ground and an essential prerequisite for selectively targeting metal‐binding proteins with small‐molecule inhibitors aiming to (i) abrogate deregulated metal‐dependent (mis)functions or (ii) leverage metal‐dyshomeostasis to selectively trigger harmful cells death.

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Establishing the catalytic and regulatory mechanism of RNA‐based machineries

Borišek

Aupič

Magistrato

2022

WIREs Comput Mol Sci

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Ribonucleoprotein (RNP)-machineries are comprised of intricate networks of long noncoding RNAs and proteins that allow them to actively participate in transcription, RNA processing, and translation. RNP-machineries thus play vital roles in gene expression and regulation. Recent advances in cryo-EM techniques provided a wealth of near-atomic-level resolution structures setting the basis for understanding how these fascinating multiscale complexes exert their diverse roles. However, these structures represent only isolated snapshots of the plastic and highly dynamic RNPmachineries and are thus insufficient to comprehensively assess their multifaceted mechanisms. In this review, we discuss the role and merit of allatom simulations in disentangling the mechanism of eukaryotic RNA-based machineries responsible for RNA processing. We showcase how all-atom simulations can capture their large-scale functional movements, trace the signaling pathways that are at the root of their massive conformational remodeling, explain recognition mechanisms of specific RNA sequences, and, lastly, unravel the chemical mechanisms underlying the formation of functional RNA strands. Finally, we review the methodological pitfalls and outline future challenges in modeling key functional aspects of these large molecular engines with all-atom simulations. In addition to providing insights into the most basic processes that govern all forms of life, in-depth mechanistic comprehension of RNP-machineries offers a foundation for developing innovative therapeutic strategies against the variety of human diseases linked to deregulated RNA metabolism. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics K E Y W O R D S cryo-EM, molecular dynamics, ribonucleoproteins, RNA catalysis, RNA processing Jure Borišek and Jana Aupič contributed equally to the study.

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JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA processing

Cited by 33 publications

References 26 publications

The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

The novel multi-cytokine inhibitor TO-207 specifically inhibits pro-inflammatory cytokine secretion in monocytes without affecting the killing ability of CAR T cells

Computing Metal‐Binding Proteins for Therapeutic Benefit

Establishing the catalytic and regulatory mechanism of RNA‐based machineries

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