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Article ; Online: Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

Craig, Robert A / De Vicente, Javier / Estrada, Anthony A / Feng, Jianwen A / Lexa, Katrina W / Canet, Mark J / Dowdle, William E / Erickson, Rebecca I / Flores, Brittany N / Haddick, Patrick C G / Kane, Lesley A / Lewcock, Joseph W / Moerke, Nathan J / Poda, Suresh B / Sweeney, Zachary / Takahashi, Ryan H / Tong, Vincent / Wang, Jing / Yulyaningsih, Ernie /

Solanoy, Hilda / Scearce-Levie, Kimberly / Sanchez, Pascal E / Tang, Liwei / Xu, Musheng / Zhang, Rui / Osipov, Maksim

Journal of medicinal chemistry

2024 Volume 67, Issue 7, Page(s) 5758–5782

Abstract: Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a ... ...

Abstract	Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.
MeSH term(s)	Humans ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism ; Mutation ; Eukaryotic Initiation Factor-2B/genetics ; Eukaryotic Initiation Factor-2B/metabolism ; Brain/metabolism ; Leukoencephalopathies/metabolism
Chemical Substances	Eukaryotic Initiation Factor-2B
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c02422
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Article ; Online: Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.

Patel, Snahel / Meilandt, William J / Erickson, Rebecca I / Chen, Jinhua / Deshmukh, Gauri / Estrada, Anthony A / Fuji, Reina N / Gibbons, Paul / Gustafson, Amy / Harris, Seth F / Imperio, Jose / Liu, Wendy / Liu, Xingrong / Liu, Yichin / Lyssikatos, Joseph P / Ma, Changyou / Yin, Jianping / Lewcock, Joseph W / Siu, Michael

Journal of medicinal chemistry

2017 Volume 60, Issue 19, Page(s) 8083–8102

Abstract: Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the ... ...

Abstract	Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.
MeSH term(s)	Alzheimer Disease/drug therapy ; Amyloid beta-Protein Precursor/biosynthesis ; Amyloid beta-Protein Precursor/genetics ; Animals ; Brain/drug effects ; Brain/metabolism ; Drug Design ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/pharmacology ; Humans ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; Macaca fascicularis ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship
Chemical Substances	Amyloid beta-Protein Precursor ; Enzyme Inhibitors ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; mitogen-activated protein kinase kinase kinase 12 (EC 2.7.11.25)
Language	English
Publishing date	2017-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.7b00843
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Article ; Online: Roles of insulin and transferrin in neural progenitor survival and proliferation.

Erickson, Rebecca I / Paucar, Andres A / Jackson, Robert L / Visnyei, Koppany / Kornblum, Harley

Journal of neuroscience research

2008 Volume 86, Issue 8, Page(s) 1884–1894

Abstract: Multipotent neural progenitor cells or neural stem cells (NSC) can be propagated in vitro from a variety of sources and have great potential for neural repair. Although it is well known that NSC divide in response to basic fibroblast growth factor (FGF-2) ...

Abstract	Multipotent neural progenitor cells or neural stem cells (NSC) can be propagated in vitro from a variety of sources and have great potential for neural repair. Although it is well known that NSC divide in response to basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF), cofactors necessary for survival and maintenance of a multipotent potential are still a matter of debate. In the current study, we examined the requirements for NSC proliferation and survival in vitro using the neurosphere culture system. Apotransferrin (TF), along with EGF and FGF-2, was sufficient for the formation of primary neurospheres derived from embryonic rat cortices. The addition of low concentrations of insulin or insulin-like growth factor-1 (IGF-1) enhanced neurosphere size and number and was necessary for continued passaging. Both insulin and IGF-1 acted at low concentrations, suggesting that their effects were mediated by their cognate receptors, both of which were expressed by neurosphere cultures. Sphere-forming progenitors survived for long periods in culture without EGF or FGF-2 when either insulin or IGF-1 was added to the media. Cell cycle analysis determined that surviving progenitors were relatively quiescent during the period without mitogens. Upon the reintroduction of EGF and FGF-2, surviving progenitors gave rise to new spheres that produced largely glial-restricted progeny compared with sister cultures. These data indicate that the neurogenic potential of NSC may be intimately linked to a continuous exposure to mitogens.
MeSH term(s)	Animals ; Cell Proliferation ; Cell Survival/physiology ; Cells, Cultured ; Female ; Insulin/physiology ; Neurons/cytology ; Neurons/physiology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Stem Cells/cytology ; Stem Cells/physiology ; Transferrin/physiology
Chemical Substances	Insulin ; Transferrin
Language	English
Publishing date	2008-02-22
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.21631
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Article ; Online: Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats.

The Journal of pharmacology and experimental therapeutics

2016 Volume 360, Issue 1, Page(s) 226–238

Abstract: Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and ... ...

Abstract	Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase ; Animals ; Dogs ; Dose-Response Relationship, Drug ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Glucose/metabolism ; Humans ; Male ; Mice ; Pancreas/drug effects ; Pancreas/metabolism ; Piperazines/toxicity ; Protein Kinase Inhibitors/toxicity ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/metabolism ; Pyridones/toxicity ; Pyrroles/toxicity ; Rats ; Species Specificity
Chemical Substances	Piperazines ; Protein Kinase Inhibitors ; Pyridones ; Pyrroles ; GDC-0853 (E9L2885WUL) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; BTK protein, human (EC 2.7.10.2) ; Btk protein, mouse (EC 2.7.10.2) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2016-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.116.236224
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Article: Neural progenitor implantation restores metabolic deficits in the brain following striatal quinolinic acid lesion.

Visnyei, Koppany / Tatsukawa, Keith J / Erickson, Rebecca I / Simonian, Sharis / Oknaian, Nareg / Carmichael, S Thomas / Kornblum, Harley I

Experimental neurology

2006 Volume 197, Issue 2, Page(s) 465–474

Abstract: Neural progenitor transplantation is a potential treatment for neurodegenerative diseases, including Huntington's disease (HD). In the current study, we tested the potential of rat embryonic neural progenitors expanded in vitro as therapy in the rat ... ...

Abstract	Neural progenitor transplantation is a potential treatment for neurodegenerative diseases, including Huntington's disease (HD). In the current study, we tested the potential of rat embryonic neural progenitors expanded in vitro as therapy in the rat quinolinic acid-lesioned striatum, a model that demonstrates some of the pathological features of HD. We used positron emission tomography (PET) to demonstrate that the intrastriatal injection of cultured rat neural progenitors results in improved metabolic function in the striatum and overlying cortex when compared to media-injected controls. Transplanted progenitors were capable of surviving, migrating long distances and differentiating into neurons and glia. The cortices of transplanted animals contained greater numbers of neurons in regions that had shown metabolic improvement. However, histological analysis revealed that only a small fraction of these increased neurons could be accounted for by engrafted cells, indicating that the metabolic sparing was likely the result of a trophic action of the transplanted cells on the host. Behavioral testing of the implanted animals did not reveal improvement in apomorphine-induced rotation. These data demonstrate that progenitor cell implantation results in enhanced metabolic function and sparing of neuron number, but that these functions do not necessarily result in the restoration of complex circuitry.
MeSH term(s)	Analysis of Variance ; Animals ; Apomorphine/pharmacology ; Autoradiography/methods ; Behavior, Animal ; Cell Count/methods ; Corpus Striatum/diagnostic imaging ; Corpus Striatum/drug effects ; Corpus Striatum/injuries ; Corpus Striatum/pathology ; Disease Models, Animal ; Embryo, Mammalian ; Functional Laterality ; Huntington Disease/chemically induced ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Huntington Disease/surgery ; Immunohistochemistry/methods ; Male ; Motor Activity/drug effects ; Neurons/physiology ; Positron-Emission Tomography/methods ; Quinolinic Acid/toxicity ; Radiography ; Rats ; Rats, Sprague-Dawley ; Recovery of Function ; Rotarod Performance Test/methods ; Stem Cell Transplantation ; Stem Cells/physiology
Chemical Substances	Quinolinic Acid (F6F0HK1URN) ; Apomorphine (N21FAR7B4S)
Language	English
Publishing date	2006-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2005.10.023
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Article ; Online: Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-α pharmacology.

Erickson, Rebecca I / Tarrant, Jacqueline / Cain, Gary / Lewin-Koh, Sock-Cheng / Dybdal, Noel / Wong, Harvey / Blackwood, Elizabeth / West, Kristina / Steigerwalt, Ronald / Mamounas, Michael / Flygare, John A / Amemiya, Kenjie / Dambach, Donna / Fairbrother, Wayne J / Diaz, Dolores

Toxicological sciences : an official journal of the Society of Toxicology

2012 Volume 131, Issue 1, Page(s) 247–258

Abstract: Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that ... ...

Abstract	Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers.
MeSH term(s)	Animals ; Antineoplastic Agents/blood ; Antineoplastic Agents/toxicity ; Chemokines/blood ; Cyclohexanes/blood ; Cyclohexanes/toxicity ; Dogs ; Female ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Liver/drug effects ; Liver/immunology ; Liver/metabolism ; Liver/pathology ; Lung/drug effects ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Male ; Pyrroles/blood ; Pyrroles/toxicity ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; Systemic Inflammatory Response Syndrome/chemically induced ; Systemic Inflammatory Response Syndrome/immunology ; Systemic Inflammatory Response Syndrome/pathology ; Toxicity Tests ; Tumor Necrosis Factor-alpha/blood ; Tumor Necrosis Factor-alpha/pharmacology
Chemical Substances	Antineoplastic Agents ; Chemokines ; Cyclohexanes ; Inhibitor of Apoptosis Proteins ; Pyrroles ; Tumor Necrosis Factor-alpha ; GDC-0152 (4KW1M48SHS)
Language	English
Publishing date	2012-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfs265
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Article ; Online: Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

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Article ; Online: Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.

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Article ; Online: Roles of insulin and transferrin in neural progenitor survival and proliferation.

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Article ; Online: Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats.

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Article: Neural progenitor implantation restores metabolic deficits in the brain following striatal quinolinic acid lesion.

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Article ; Online: Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-α pharmacology.

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