A5043073655- Wnt/β-catenin signaling in development and cancer
- Lysosomal Storage Disorders Research
- Enzyme function and inhibition
- PI3K/AKT/mTOR signaling in cancer
- Cellular transport and secretion
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Trypanosoma species research and implications
- Cancer-related gene regulation
- Protein Kinase Regulation and GTPase Signaling
- Mechanisms of cancer metastasis
- Drug-Induced Hepatotoxicity and Protection
- Pharmacogenetics and Drug Metabolism
- Parkinson's Disease Mechanisms and Treatments
- Carcinogens and Genotoxicity Assessment
- Cancer Cells and Metastasis
- Cancer-related Molecular Pathways
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Cell Adhesion Molecules Research
- Alzheimer's disease research and treatments
- Sarcoma Diagnosis and Treatment
- Melanoma and MAPK Pathways
- PARP inhibition in cancer therapy
- Biomedical Research and Pathophysiology
- Biosimilars and Bioanalytical Methods
Denali Therapeutics (United States)
2017-2023
Texas Tech University
2013-2015
Texas Tech University Health Sciences Center
2013-2015
Array BioPharma (United States)
2014
Oslo University Hospital
2013
Czech Academy of Sciences, Institute of Molecular Genetics
2013
Czech Academy of Sciences
2013
Genentech
2012
Center for Effective Philanthropy
2004-2007
Seattle University
2006
Abstract Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin–mediated signaling. However, continued requirement Wnt/β-catenin signaling for tumor progression in the context acquired KRAS and other is less well-established. To attenuate tumors, we have developed potent specific small-molecule tankyrase inhibitors, G007-LK G244-LM, that reduce preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization....
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 activity is thought to impair lysosomal function and may contribute pathogenesis of PD. Thus, inhibition a potential disease-modifying therapeutic strategy DNL201 an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule inhibitor. In preclinical models, inhibited as evidenced by reduced phosphorylation both at serine-935...
An enzyme transport vehicle enables brain delivery of lysosomal enzymes across the blood-brain barrier in mice.
Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).The aim this study was to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants patients with PD.Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 (DNLI-C-0001) evaluated single multiple doses up 28 days participants. 1b...
The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS upstream signaling. While targeting nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of pathway. Simultaneous multiple pathway, such as ERK, offers prospect enhanced efficacy well reduced potential for acquired resistance. Described...
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported A-1155463 using structure-based drug design. Key design elements included rigidification pharmacophore introduction sp3-rich moieties capable generating highly productive interactions within key P4 pocket BCL-XL. A-1331852 has since been used as...
Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...
Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in treatment benign vascular tumors such as infantile hemangiomas. As hemangiomas are reported to express high levels beta adrenergic receptors, we examined expression these on more aggressive hemangioendotheliomas and angiosarcomas, revealing 1, 2, 3 were indeed present therefore may similarly show increased susceptibility inhibitory effects blockade. Using a panel hemangioendothelioma angiosarcoma...
Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase are being explored as potential anticancer agents. also critical for intestinal tissue homeostasis, and inhibitors have been shown to cause toxicity in mice by affecting stem cells. This study sought characterize the of reversibility, assess their therapeutic index. Novel inhibitor G-631 caused dose-dependent a index < 1 after 14 days dosing mice. At tolerated subtherapeutic...
p21-activated kinase 1 (PAK1) has an important role in transducing signals several oncogenic pathways. The concept of inhibiting this garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity a narrow therapeutic window. To attempt mitigating toxicity, we introduced structural changes,...
In vitro skin model systems are increasingly being used both in the early evaluation of therapeutic drug candidates and confirmatory mechanistic studies. The most commonly these reconstituted human epidermis (RHE) models. These RHE models consist solely epidermal keratinocytes, which comes with some limitations but also advantage focusing toxicologic pharmacologic on keratinocytes alone. can generally be implemented more quickly, easily, reproducibly than vivo thus for high throughput...
Mucopolysaccharidosis type II is a lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS) and characterized the accumulation primary substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS (nMPS II) has been hindered lack CNS biomarkers. Characterization fluid biomarkers largely focused on evaluating GAGs cerebrospinal (CSF) periphery; however, GAG levels alone do not accurately reflect broad cellular...
Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in glycolysis and a key molecule involved maintaining cellular energy metabolism. phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of important salvage pathway which nicotinamide recycled into NAD. NAMPT up-regulated many types cancer inhibitors (NAMPTi) have potential therapeutic benefit by impairing tumor Clinical trials with NAMPTi APO-866 GMX-1778, however, failed to reach projected efficacious exposures...
Infantile hemangiomas are benign vascular tumors primarily found on the skin in 10% of pediatric population. The etiology this disease is largely unknown and while large scale genomic studies have examined transcriptomes infantile hemangioma as a whole, no study to date has compared global gene expression profiles pure endothelial cells (HEMECs) that normal human dermal microvascular (HDMVECs).To shed light molecular differences between these aberrant cell types, we performed whole genome...
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation glycosaminoglycans (GAGs) throughout body. Treatment MPS remains considerable challenge as current enzyme replacement therapies do not adequately control many aspects disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that engineered to bind transferrin receptor; this...
MEK, a kinase downstream of Ras and Raf oncogenes, constitutes high priority target in oncology research. MEK small molecule inhibitors cause soft tissue mineralization rats secondary to serum inorganic phosphorus (iP) elevation, but the molecular mechanism for this toxicity remains undetermined. We performed investigative studies with structurally distinct GEN-A PD325901 (PD-901) Sprague-Dawley rats. Our data support that involves FGF-23 signal blockade rat kidney, causing transcriptional...