John Liles - Moonwalk Biosciences | LinkedIn (original) (raw)
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Drug discovery biologist and leader with proven success advancing novel therapeutics from…
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Moonwalk Biosciences
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Publications
The Journal of Clinical Investigation July 19, 2018
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. Herein, we describe the discovery and characterization of a potent and selective small molecule inhibitor of ASK1…
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. Herein, we describe the discovery and characterization of a potent and selective small molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted decline of glomerular filtration rate. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of diabetic kidney disease
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Am J Respir Crit Care Med Sep 2017
RATIONALE Progression of pulmonary arterial hypertension (PAH) is associated with pathologic remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of mitogenactivated protein kinases (MAPKs) which stimulate apoptosis, inflammation and fibrosis. OBJECTIVES We investigated whether pharmacological inhibition of the redoxsensitive apical MAPK Apoptosis Signal-Regulating Kinase 1 (ASK1) can halt the progression of…
RATIONALE Progression of pulmonary arterial hypertension (PAH) is associated with pathologic remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of mitogenactivated protein kinases (MAPKs) which stimulate apoptosis, inflammation and fibrosis. OBJECTIVES We investigated whether pharmacological inhibition of the redoxsensitive apical MAPK Apoptosis Signal-Regulating Kinase 1 (ASK1) can halt the progression of pulmonary vascular and RV remodeling. METHODS AND RESULTS Oral administration of a selective ASK1 inhibitor, GS-444217, dose-dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in two rat models of PAH (monocrotaline; MCT, and Sugen/Hypoxia; Su/Hx). Therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease. ASK1 inhibition also directly reduced cardiac fibrosis and RV hypertrophy and improved cardiac function in a murine model of RV pressure overload induced by pulmonary artery banding (PAB). In cellular models, GS-444217 reduced phosphorylation of p38 and JNK induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts (isolated directly out of the RV) and human pulmonary adventitial fibroblasts derived from PAH patients. CONCLUSIONS ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the RV and halted progression of PH in rodent models. These preclinical data provide the first description of a causal role of ASK1 in PAH disease pathogenesis.
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Diabetes Nov 2015
p38 mitogen-activated protein kinase (MAPK) signaling promotes diabetic kidney injury. Apoptosis signal-regulating kinase (ASK)1 is one of the upstream kinases in the p38 MAPK-signaling pathway, which is activated by inflammation and oxidative stress, suggesting a possible role for ASK1 in diabetic nephropathy. In this study, we examined whether a selective ASK1 inhibitor can prevent the induction and progression of diabetic nephropathy in mice. Diabetes was induced in hypertensive endothelial…
p38 mitogen-activated protein kinase (MAPK) signaling promotes diabetic kidney injury. Apoptosis signal-regulating kinase (ASK)1 is one of the upstream kinases in the p38 MAPK-signaling pathway, which is activated by inflammation and oxidative stress, suggesting a possible role for ASK1 in diabetic nephropathy. In this study, we examined whether a selective ASK1 inhibitor can prevent the induction and progression of diabetic nephropathy in mice. Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by five low-dose streptozotocin (STZ) injections. Groups of diabetic Nos3−/− mice received ASK1 inhibitor (GS-444217 delivered in chow) as an early intervention (2–8 weeks after STZ) or late intervention (weeks 8–15 after STZ). Control diabetic and nondiabetic Nos3−/− mice received normal chow. Treatment with GS-444217 abrogated p38 MAPK activation in diabetic kidneys but had no effect upon hypertension in Nos3−/− mice. Early intervention with GS-444217 significantly inhibited diabetic glomerulosclerosis and reduced renal dysfunction but had no effect on the development of albuminuria. Late intervention with GS-444217 improved renal function and halted the progression of glomerulosclerosis, renal inflammation, and tubular injury despite having no effect on established albuminuria. In conclusion, this study identifies ASK1 as a new therapeutic target in diabetic nephropathy to reduce renal inflammation and fibrosis independent of blood pressure control.
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Patents
Issued December 5, 2023 US11833150B2
The present disclosure relates to a method of preventing and/or treating liver disease comprising administering an ACC inhibitor in combination with an FXR agonist to a patient in need thereof.
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Issued March 26, 2019 US10238636B2
The present disclosure relates to a method of preventing and/or treating liver disease comprising administering an ASK1 inhibitor in combination with a FXR agonist to a patient in need thereof.
Other inventors
Issued February 18, 2016 WO2016025474A1
The present disclosure relates to a method of preventing and/or treating pulmonary vascular disease and/or right ventricular dysfunction, including but not limited to pulmonary hypertension or pulmonary arterial hypertension, comprising administering a therapeutically effective amount of an ASK1 inhibitor
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Projects
Stanford Rebuild - Innovating for a post COVID-19 future
Jun 2020 - Sep 2020
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Congratulations to Rigel Kishton for delivering a great presentation in San Antonio highlighting Moonwalk Biosciences' innovative epigenetic…
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Rigel Kishton did a great job presenting Moonwalk’s first data on an epigenetic atlas of adipocytes at ObesityWeek® 2024 in San Antonio! #obesityweek
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Today we announced that Jade has entered into a definitive merger agreement with Aerovate Therapeutics. In support of the merger, we have secured…
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We're thrilled to share our recent publication in Journal of Hepatology regarding the potential of ACMSD inhibition in #MASH. In addition to…
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If you are looking for a preclinical model of #PKD you can drop by Maria Ougaards poster FR-PO599 at #ASN #KidneyWK and learn how we apply 3D imaging…
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Day 2! #kidneyweek2024!
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We’re excited to welcome Tom Frohlich as our new CEO and Hetal Kocinsky, M.D. as CMO. Their combined expertise in drug development and business…
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I'm extremely slow to post this but wanted to acknowledge a few people while I'm still energized from attending the Bloom Burton Award Gala recently.…
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