Development of 1-((1,4-<i>trans</i>)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response

Yefidoff-Freedman, Revital; Fan, Jing; Lü, Yan; Zhang, Qingwen; Santos, Guillermo Rodrigo Reis dos; Rana, Sandeep; Contreras, Jacob I.; Sahoo, Rupam; Wan, Debin; Young, J.O.; Teixeira, Karina Luiza Dias; Morisseau, Christophe; Halperin, José A.; Hammock, Bruce D.; Natarajan, Amarnath; Wang, Peimin; Chorev, Michael; Aktas, Bertal H.

doi:10.1021/acs.jmedchem.7b00059

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…Notably, disruption of HRI signaling appears to be well-tolerated in vivo , as HRI -/- mice were found to be completely normal and fertile, with only mild hematologic abnormalities ( 10 ). Considerable progress has recently been made toward developing specific HRI modulators ( 57 ), and our work supports this continued pursuit.…”

Section: Discussionsupporting

confidence: 62%

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

White

Schroeder²,

Zhu

et al. 2018

Oncogene

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Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of 10 human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib-resistant cell lines displayed increased phosphorylation of eIF2α, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2α kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2α as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance.

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Section: Discussionsupporting

confidence: 62%

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

White

Schroeder²,

Zhu

et al. 2018

Oncogene

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“…No target-dependent toxicities have emerged with direct HRI activation [33,34], while there are reports of secondary benefits of HRI activation in models of human disease including beta-thalassemia and fatty liver disease [26,70,71]. Other small-molecule compounds that phosphorylate eIF2α in vivo and reduce tumor growth are known to be well tolerated, such as eicosapentaenoic acid, a main component of fish oils [42].…”

Section: Expert Opinionmentioning

confidence: 99%

“…As prefaced above, stress-induced activation of eIF2α phosphorylation can direct adaptation to cellular stress and a prosurvival outcome [15]. Despite these concerns, in vivo studies of specific HRI activators, including N,N′-diarylurea and cHAU compounds [33,34] demonstrate that pharmacologic induction of eIF2α phosphorylation can inhibit tumor growth at nontoxic doses. The ability of HRI activators to provide intense and sustained eIF2α phosphorylation to trigger an apoptotic response is likely critical to an anticancer outcome.…”

Section: Expert Opinionmentioning

confidence: 99%

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The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Burwick

Aktas

2017

Expert Opinion on Therapeutic Targets

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Introduction The eIF2α kinase heme-regulated inhibitor (HRI) is one of four well-described kinases that phosphorylate eIF2α in response to various cell stressors, resulting in reduced ternary complex formation and attenuation of mRNA translation. Although HRI is well known for its role as a heme sensor in erythroid progenitors, pharmacologic activation of HRI has been demonstrated to have anti-cancer activity across a wide range of tumor sub-types. Here, the potential of HRI activators as novel cancer therapeutics is explored. Areas covered We provide an introduction to eIF2 signaling pathways in general, and specifically review data on the eIF2α kinase HRI in erythroid and non-erythroid cells. We review aspects of targeting eIF2 signaling in cancer and highlight promising data using HRI activators against tumor cells. Expert opinion Pharmacologic activation of HRI inhibits tumor growth as a single agent without appreciable toxicity in vivo. The ability of HRI activators to provide direct and sustained eIF2α phosphorylation without inducing oxidative stress or broad eIF2α kinase activation may be especially advantageous for tolerability. Combination therapy with established therapeutics may further augment anti-cancer activity to overcome disease resistance.

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“…Urea derivatives, particularly those substituted by cyclic rings, provide significant opportunities for drug development and some of them have been previously shown to trigger eIF2α phosphorylation in mammalian cells 22 – 24 , a key event in the stress response and cell survival, especially for cancer cells chemotherapy 25 . Some urea derivatives were found to activate the heme-regulated kinase, one of the four mammalian kinases that phosphorylate eIF2α, arresting cancer cell proliferation 26 . In addition, other substituted ureas could inhibit several enzymes 27 , prevent cellular growth 28 and interfere with activation of intracellular complexes 29 .…”

Section: Introductionmentioning

confidence: 99%

Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Machado

Franco

Neto

et al. 2018

Sci Rep

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Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against Trypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of T. cruzi inside mammalian cells with an EC50 of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma brucei bloodstream and procyclic forms) at similar doses. It caused changes in the T. cruzi morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.

show abstract

Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme-Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2α) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response

Cited by 18 publications

References 33 publications

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

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