Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase

Rosen, Mark D.; Woods, Craig R.; Goldberg, Steven D.; Hack, Michael D.; Bounds, A. Dawn; Yang, Young Chul; Wagaman, Pamela C.; Phuong, Victor K.; Ameriks, Angela P.; Barrett, Terrance D.; Kanelakis, Kimon C.; Chang, Jui‐Yoa; Shankley, Nigel P.; Rabinowitz, Michael H.

doi:10.1016/j.bmcl.2009.10.033

Cited by 38 publications

(29 citation statements)

References 16 publications

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“…HRI is an especially attractive target since it is not required for responses to non-pathogens but interferes with specific virulence mechanisms. Recently, it has been shown that HRI activity can be reduced by either direct targeting with small molecules or indirectly by using natural products that inhibit the HRI-cofactor Hsp90 [28–30]. The targeting of host factors may make it less likely that a pathogen would evolve drug-resistance since the pathogen would not have genetic control over the interaction between the compound and its target.…”

Section: Discussionmentioning

confidence: 99%

The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens

et al. 2013

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Here we show that cells lacking the heme-regulated inhibitor (HRI) are highly resistant to infection by bacterial pathogens. By examining the infection process in wild-type and HRI null cells, we found that HRI is required for pathogens to execute their virulence-associated cellular activities. Specifically, unlike wild-type cells, HRI null cells infected with the gram-negative bacterial pathogen Yersinia are essentially impervious to the cytoskeleton-damaging effects of the Yop virulence factors. This effect is due to reduced functioning of the Yersinia type 3 secretion (T3S) system which injects virulence factors directly into the host cell cytosol. Reduced T3S activity is also observed in HRI null cells infected with the bacterial pathogen Chlamydia which results in a dramatic reduction in its intracellular proliferation. We go on to show that a HRI-mediated process plays a central role in the cellular infection cycle of the Gram-positive pathogen Listeria . For this pathogen, HRI is required for the post-invasion trafficking of the bacterium to the infected host cytosol. Thus by depriving Listeria of its intracellular niche, there is a highly reduced proliferation of Listeria in HRI null cells. We provide evidence that these infection-associated functions of HRI (an eIF2α kinase) are independent of its activity as a regulator of protein synthesis. This is the first report of a host factor whose absence interferes with the function of T3S secretion and cytosolic access by pathogens and makes HRI an excellent target for inhibitors due to its broad virulence-associated activities.

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Section: Discussionmentioning

confidence: 99%

The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens

et al. 2013

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“…A series of aminopyrazoloindane ATP-competitive HRI inhibitors have been reported [64]. These compounds were identified in a screen using recombinant full-length human HRI.…”

Section: Inhibitors Of Hrimentioning

confidence: 99%

Targeting the ATF4 pathway in cancer therapy

Singleton

Harris

2012

Expert Opinion on Therapeutic Targets

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“…Au cours de ces dernières années, des molécules permettant d'inhiber HRI dans une perspective thérapeu-tique ont été développées. Une équipe a développé des aminopyrazolindanes, qui inhibent HRI in vitro en entrant en compétition avec l'ATP, mais les essais effectués chez les rats ont montré une faible biodisponibilité [43]. Des études de relations structure-activité ont permis d'améliorer les propriétés pharmacodynamiques de la molécule de départ.…”

Section: Développement De Drogues Influençant L'expression De Hri Dévunclassified

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

2014

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Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase

Cited by 38 publications

References 16 publications

The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens

The Host-Encoded Heme Regulated Inhibitor (HRI) Facilitates Virulence-Associated Activities of Bacterial Pathogens

Targeting the ATF4 pathway in cancer therapy

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

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