CMS121 / Salk Institute, Virogenics - LARVOL DELTA

The impact of fatty acid synthase on HSV-1 infection dynamics. (PubMed, PLoS Pathog) - "Conversely, silencing FASN or applying FASN inhibitors (i.e., CMS121 and C75) markedly reduces the infectivity of newly released HSV-1 virions, suggesting that while initial replication remains unaffected, FASN is crucial for maintaining virion structure and facilitating entry into host cells...Blocking CD36 function with SSO further decreased viral infectivity, demonstrating the critical role of lipid uptake in HSV-1 life cycle. Altogether, our findings reveal how HSV-1 manipulates lipid metabolism, offering insights into its association with chronic disease and therapeutic intervention."

Journal • Herpes Simplex • Infectious Disease • Metabolic Disorders • CD36 • FASN • SCARB1

Long noncoding RNA ZRANB2-AS2 promotes endothelial cell dysfunction by inhibiting phosphorylation of acetyl-CoA carboxylase 1 in diabetes. (PubMed, Exp Cell Res) - "We further established the rescue assay by adding CMS-121, a specific ACC1 inhibitor...We conducted in vivo experiments to determine the inhibitory effect of lncRNA ZRANB2-AS2 in diabetic mice model. Lnc ZRANB2-AS2 inhibits cell proliferation, migration and angiogenesis while accelerates apoptosis of endothelial cells by regulating the phosphorylation of acetyl-CoA carboxylase 1 in diabetes."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • ACACA

Safety, Pharmacokinetics, and Cardiodynamics of CMS121, a Novel Small Molecule Fisetin Derivative with Neuroprotective Properties, in Phase 1 Healthy Adult Volunteers. (PubMed, medRxiv) - "There is a significant effect of age on the pharmacokinetics of CMS121 and its metabolites, with higher systemic exposures to CMS121 and its metabolites and longer terminal elimination half-lives in elderly subjects. Systemic exposures to CMS121 were higher in the fed state by approximately 50%."

Journal • P1 data • PK/PD data

CMS121, a Novel Drug Candidate for the Treatment of Alzheimer's Disease and Age-Related Dementia. (PubMed, J Alzheimers Dis) - "Furthermore, we identified a key target of CMS121 as fatty acid synthase, a protein which had not been previously considered in the context of AD. Herein, we provide a comprehensive description of the development of CMS121, its preclinical activities, and the results of the toxicology testing that led to its IND approval."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • FASN

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction. (PubMed, Aging (Albany NY)) - "The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CASP1 • CASP3 • NOX4 • NRF1 • SLC2A4 • TFAM

ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARα- CPT1A axis. (PubMed, J Transl Med) - "Targeting ACACA can reduce lipid accumulation by mediating the AMPK- PPARα- CPT1A pathway, which regulates lipid metabolism and alleviates mitochondrial dysfunction."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • ACACA • AMPK • CPT1A • PPARA

CMS121 Partially Attenuates Disease Progression in Mouse Models of Huntington's Disease. (PubMed, Mol Neurobiol) - "CMS121 also reduced HD-driven changes in the expression of genes associated with the proteasome and oxidative phosphorylation. Overall, these results suggest that CMS121 could provide some benefits for HD patients, particularly with regard to increasing health span."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Diabetes • Huntington's Disease • Ischemic stroke • Metabolic Disorders • Movement Disorders

Attenuation of Age-Related Hearing Impairment in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated with Fatty Acid Synthase Inhibitor CMS121. (PubMed, J Mol Neurosci) - "Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014. Our study shows a significant reduction in ABR threshold shifts and increased preservation of IHC ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice."

Journal • Preclinical • Otorhinolaryngology • FASN

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice. (PubMed, Int J Mol Sci) - "Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Diabetes • Genetic Disorders • Hepatology • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • CASP3 • CLU • IL18 • LEP • LEPR • NFKB1 • NF-κβ

Safety, Tolerability and Pharmacokinetics of CMS121, a Drug Candidate for Alzheimer's Disease, in Healthy Subjects (clinicaltrials.gov) - P1 | N=99 | Completed | Sponsor: Virogenics, Inc. | Recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

Cms121 partially attenuates disease progression in the r6/2 and yac128 mouse models of Huntington’s disease (Neuroscience 2022) - "Thus, while CMS121 slowed disease progression, it was not sufficient to stop it in the mouse models used in this study. This suggests that testing combinations of drug candidates that together target a wider range of pathways implicated in HD could be a very promising approach to treating this disease."

Preclinical • CNS Disorders

Safety, Tolerability and Pharmacokinetics of CMS121, a Drug Candidate for Alzheimer's Disease, in Healthy Subjects (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Virogenics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders