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Last update 23 Jan 2025

DHX33

Last update 23 Jan 2025

Basic Info

Synonyms

ATP-dependent RNA helicase DHX33, DDX33, DEAH box protein 33

+ [4]

Introduction

Implicated in nucleolar organization, ribosome biogenesis, protein synthesis and cytoplasmic dsRNA sensing (By similarity) (PubMed:21930779, PubMed:23871209, PubMed:26100019). Stimulates RNA polymerase I transcription of the 47S precursor rRNA. Associates with ribosomal DNA (rDNA) loci where it is involved in POLR1A recruitment (PubMed:21930779). In the cytoplasm, promotes elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation (PubMed:26100019). Senses cytosolic dsRNA mediating NLRP3 inflammasome formation in macrophages and type I interferon production in myeloid dendritic cells (PubMed:23871209). Required for NLRP3 activation induced by viral dsRNA and bacterial RNA (PubMed:23871209). In dendritic cells, required for induction of type I interferon production induced by cytoplasmic dsRNA via the activation of MAPK and NF-kappa-B signaling pathways (By similarity).

Drugs associated with DHX33

KY-386

Target

DHX33

Mechanism

DHX33 inhibitors

Active Org.

Shenzhen KeYe Life Technologies, Co., LtdStartup

Originator Org.

Shenzhen KeYe Life Technologies, Co., LtdStartup

Active Indication

Advanced Malignant Solid Neoplasm [+3]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with DHX33

CTR20243710

/ Not yet recruitingPhase 1

一项评估KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的安全性、耐受性、药代动力学和初步抗肿瘤活性的开放性、剂量递增和剂量扩展的I期研究

[Translation] An open-label, dose-escalation and dose-expansion Phase I study to evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of KY386 in patients with DHX33-positive relapsed/refractory advanced malignant solid tumors

剂量递增阶段：主要目的：评估KY386在复发/难治性晚期恶性实体瘤患者中的安全性、耐受性和剂量限制性毒性。确定KY386治疗复发/难治性晚期恶性实体瘤患者的最大耐受剂量/最大给药剂量和扩展期推荐剂量。次要目的：评估KY386在复发/难治性晚期恶性实体瘤患者中的药代动力学特征。评估KY386在复发/难治性晚期恶性实体瘤患者中的初步抗肿瘤活性。剂量扩展阶段：主要目的：评估KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的安全性、耐受性和初步抗肿瘤活性。确定KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的II期临床研究推荐剂量。次要目的：评估KY386在DHX33阳性的复发/难治性晚期恶性实体瘤患者中的PK特征。探索性目的（适用于各阶段）：探索KY386的暴露量/剂量与安全性以及临床疗效之间的关系。探索KY386的药效动力学特征。

[Translation]

Dose escalation phase: Primary objective: To evaluate the safety, tolerability and dose-limiting toxicity of KY386 in patients with relapsed/refractory advanced malignant solid tumors. To determine the maximum tolerated dose/maximum dose and recommended dose for the expansion phase of KY386 in patients with relapsed/refractory advanced malignant solid tumors. Secondary objective: To evaluate the pharmacokinetic characteristics of KY386 in patients with relapsed/refractory advanced malignant solid tumors. To evaluate the preliminary anti-tumor activity of KY386 in patients with relapsed/refractory advanced malignant solid tumors. Dose expansion phase: Primary objective: To evaluate the safety, tolerability and preliminary anti-tumor activity of KY386 in patients with DHX33-positive relapsed/refractory advanced malignant solid tumors. To determine the recommended dose for Phase II clinical study of KY386 in patients with DHX33-positive relapsed/refractory advanced malignant solid tumors. Secondary objective: To evaluate the PK characteristics of KY386 in patients with DHX33-positive relapsed/refractory advanced malignant solid tumors. Exploratory objective (applicable to all phases): To explore the relationship between exposure/dose and safety and clinical efficacy of KY386. Explore the pharmacodynamic characteristics of KY386.

Start Date-

Sponsor / Collaborator

Shenzhen KeYe Life Technologies, Co., LtdStartup

100 Clinical Results associated with DHX33

100 Translational Medicine associated with DHX33

0 Patents (Medical) associated with DHX33

104

Literatures (Medical) associated with DHX33

02 Jul 2024·ACS Omega

An RNA Helicase DHX33 Inhibitor Shows Broad Anticancer Activity via Inducing Ferroptosis in Cancer Cells

Article

Author: Wen, Fuyu ; Liang, Yingying ; Deng, Yuanlian ; Zhang, Yandong ; Liao, Deqing ; Tang, Xiyu

RNA helicase DHX33 has been identified as a critical factor promoting cancer development. In the present study, a previously developed small molecule inhibitor for DHX33, KY386, was found to robustly kill cancer cells via a new path, the ferroptosis pathway. Mechanistically, DHX33 promotes the expression of critical players in lipid metabolism including FADS1, FADS2, and SCD1 genes, thereby sensitizing cancer cells to ferroptosis mediated cell death. Our study reveals a novel mechanism of DHX33 in promoting tumorigenesis and highlights that pharmacological targeting DHX33 can be a feasible option in human cancers. Normally differentiated cells are insensitive to DHX33 inhibition, and DHX33 inhibitors have little cellular toxicity in vitro and in vivo. Our studies demonstrated that DHX33 inhibitors can be promising anticancer agents with great potential for cancer treatment.

31 May 2024·The Journal of Biochemistry

Formation of the NLRP3 inflammasome inhibits stress granule assembly by multiple mechanisms

Article

Author: Takekawa, Mutsuhiro ; Nakamura, Takanori ; Kubota, Yuji ; Yoshioka, Daisuke

AbstractProper regulation of cellular response to environmental stress is crucial for maintaining biological homeostasis and is achieved by the balance between cell death processes, such as the formation of the pyroptosis-inducing NLRP3 inflammasome, and pro-survival processes, such as stress granule (SG) assembly. However, the functional interplay between these two stress-responsive organelles remains elusive. Here, we identified DHX33, a viral RNA sensor for the NLRP3 inflammasome, as a SG component, and the SG-nucleating protein G3BP as an NLRP3 inflammasome component. We also found that a decrease in intracellular potassium (K+) concentration, a key ‘common’ step in NLRP3 inflammasome activation, markedly inhibited SG assembly. Therefore, when macrophages are exposed to stress stimuli with the potential to induce both SGs and the NLRP3 inflammasome, such as cytoplasmic poly(I:C) stimulation, they preferentially form the NLRP3 inflammasome but avoid SG assembly by sequestering G3BP into the inflammasome and by inducing a reduction in intracellular K+ levels. Thus, under such conditions, DHX33 is primarily utilized as a viral RNA sensor for the inflammasome. Our data reveal the functional crosstalk between NLRP3 inflammasome-mediated pyroptosis and SG-mediated cell survival pathways and delineate a molecular mechanism that regulates cell-fate decisions and anti-viral innate immunity under stress.

16 May 2024·Oncotarget

The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response

Article

Author: Sauvageau, Martin ; Toutant, Johanne ; Tyers, Mike ; Huard, Caroline ; Gravel-Trudeau, Alice ; Salvetti, Anna ; Shkreta, Lulzim ; Ehresmann, Sophie ; Grierson, David ; Comeau, Christian ; Boudreault, Pierre-Luc ; Delannoy, Aurélie ; Coulombe-Huntington, Jasmin ; Chabot, Benoit ; Delbrouck, Julien A ; Durantel, David

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.

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