Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity

Yao, Chen; Johnson, William M.; Gao, Yue; Wang, Wen; Zhang, Jinwei; Deák, Mária; Alessi, Dario R.; Zhu, Xiongwei; Mieyal, John J.; Roder, Hanno M.; Wilson-Delfosse, Amy L.; Chen, Shu G.

doi:10.1093/hmg/dds431

Cited by 70 publications

(64 citation statements)

References 36 publications

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“…29 To determine whether TTT-3002 targets FLT3 kinase activity and inhibits autophosphorylation, we studied the effect of TTT-3002 treatment on the FLT3/ITD-expressing human leukemia cell lines Molm14 and MV4-11. Cells were subjected to 1 hour of treatment with increasing concentrations of TTT-3002 or AC220, previously the most potent published FLT3 TKI.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, it may be a fairly selective FLT3 inhibitor under a realistic clinical dosing regimen. Indeed, when profiled against a panel of 140 kinases by Yao et al, 29 TTT-3002 has a rather high degree of selectivity in vitro. In our studies with TTT-3002, we observed an IC 90 of 1 nM against FLT3/ITD phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, given the observation that ,1% of kinases in this panel are targeted at the IC 90 of FLT3/ITD, and only about 11% of kinases are targeted at a concentration 10-fold higher than this IC 90 concentration, we feel that this compound is relatively selective for activity against FLT3. 29 While mice with complete genetic knock-out of Flt3 have only subtle deficits in hematopoietic stem cell activity, combination with partial inactivating c-Kit mutation results in severe hematopoietic stem cell defects. 32 Thus, it is desirable that FLT3 TKIs not have significant activity against c-Kit because combination trials with chemotherapy would likely result in delayed hematopoietic recovery.…”

Section: Discussionmentioning

confidence: 99%

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TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

Ma¹,

Nguyen²,

Li³

et al. 2014

Blood

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Key Points• A novel TKI is discovered with potent and selective activity against FLT3-mutant cell lines and primary patient samples.• TTT-3002 is effective in vivo in several mouse tumor models of FLT3/ITDassociated AML with minimal toxicity.More than 35% of acute myeloid leukemia (AML) patients harbor a constitutively activating mutation in FMS-like tyrosine kinase-3 (FLT3). The most common type, internal tandem duplication (ITD), confers poor prognosis. We report for the first time on TTT-3002, a tyrosine kinase inhibitor (TKI) that is one of the most potent FLT3 inhibitors discovered to date. Studies using human FLT3/ITD mutant leukemia cell lines revealed the half maximal inhibitory concentration (IC 50 ) for inhibiting FLT3 autophosphorylation is from 100 to 250 pM. The proliferation IC 50 for TTT-3002 in these same cells was from 490 to 920 pM. TTT-3002 also showed potent activity when tested against the most frequently occurring FLT3-activating point mutation, FLT3/D835Y, against which many current TKIs are ineffective. These findings were validated in vivo by using mouse models of FLT3-associated AML. Survival and tumor burden of mice in several FLT3/ITD transplantation models is significantly improved by administration of TTT-3002 via oral dosing. Finally, we demonstrated that TTT-3002 is cytotoxic to leukemic blasts isolated from FLT3/ITD-expressing AML patients, while displaying minimal toxicity to normal hematopoietic stem/progenitor cells from healthy blood and bone marrow donors. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI in the treatment of FLT3-mutant AML. (Blood. 2014;123(10):1525-1534

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

Ma¹,

Nguyen²,

Li³

et al. 2014

Blood

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“…Furthermore, overexpression of K1347A LRRK2, a GTP binding-deficient mutant with impaired kinase activity, did not induce dopaminergic neurodegeneration or behavioral deficits. Yao and coworkers have also demonstrated that pharmacological inhibition of LRRK2 kinase activity rescued dopaminergic neurodegeneration and dopamine-mediated behavioral deficits in worms overexpressing R1441C or G2019S LRRK2 (Yao et al 2013). These observations support a role for kinase activity as a critical mediator of neurotoxicity induced by R1441C and G2019S mutant LRRK2 in worm models.…”

Section: Caenorhabditis Elegansmentioning

confidence: 96%

Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents

Daniel

Moore

2014

Current Topics in Behavioral Neurosciences

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Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8) gene represent the most common cause of familial Parkinson's disease (PD) with autosomal dominant inheritance, whereas common variation at the LRRK2 genomic locus influences the risk of developing idiopathic PD. LRRK2 is a member of the ROCO protein family and contains multiple domains, including Ras-of-Complex (ROC) GTPase, kinase, and protein-protein interaction domains. In the last decade, the biochemical characterization of LRRK2 and the development of animal model s have provided important insight into the pathobiology of LRRK2. In this review, we comprehensively describe the different models employed to understand LRRK2-associated PD, including yeast, invertebrates, transgenic and viral-based rodents, and patient-derived induced pluripotent stem cells. We discuss how these models have contributed to understanding LRRK2 pathobiology and the advantages and limitations of each model for exploring aspects of LRRK2-associated PD.

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“…Studies have also shown that LRRK2-IN-1 and other LRRK2 inhibitors mediate protection against LRRK2 toxicity in vivo. Specifically, both LRRK2-IN-1 and TTT-3002, another small molecule LRRK2-kinase inhibitor, were shown to protect dopaminergic neurons in C. elegans models of PD involving mutant LRRK2 expression [27] . This protection demonstrated the in vivo efficacy of small molecule kinase inhibitors against LRRK2 toxicity.…”

Section: Overview Of Parkinson's Disease and The Role Of Oxidative Stmentioning

confidence: 99%

The Roles of Redox Enzymes in Parkinson’s Disease: Focus on Glutaredoxin

Johnson

Wilson-Delfosse

Chen

et al. 2015

Ther Targets Neurol Dis

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Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo.

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Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity

Cited by 70 publications

References 36 publications

TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents

The Roles of Redox Enzymes in Parkinson’s Disease: Focus on Glutaredoxin

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