Drug intelligence / Profile preview

withanolide a

Development stage
Preclinical
Modality
Small Molecules
Administration
Oral
01

Overview

Withanolide A is a naturally occurring steroidal lactone, classified as a withanolide, primarily isolated from plants such as Withania somnifera (ashwagandha), Withania coagulans, and Discopodium penninervium[4]. It is one of the most studied withanolides and is recognized for a broad range of biological activities including antitumor, anti-inflammatory, antioxidant, immunomodulatory, neuroregenerative, and cytoprotective effects[1]. Mechanistically, withanolide A and related compounds have been shown to: - Inhibit key inflammatory and oncogenic signaling pathways (notably NF-κB, JAK/STAT, AP-1, PI3K/Akt/mTOR, PPARγ, Hsp90, Nrf2, and HIF-1)[1]. - Downregulate beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and upregulate ADAM10 and insulin-degrading enzyme[1], with specific neuroregenerative effects relevant to neurodegenerative diseases such as Alzheimer’s disease. - Act as an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)[1]. Withanolide A’s diverse activity profile is attributed to its reactive structural features: an α,β-unsaturated ketone in ring A, a 5β,6β-epoxide in ring B, and a lactone side chain[6]. It is studied primarily as a natural product for its therapeutic applications in inflammation-mediated chronic diseases (including autoimmune disorders, cancer, and neurodegenerative diseases). While preclinical data is promising, robust clinical trial data in humans is lacking[1].

Other names
withanolide A(+)-withanolide A32911-62-9V903234S8GV-903234S8GV 903234S8G
02

Targets

AcetylcholinesteraseBACE1 (Beta-site APP-cleaving enzyme 1)ButyrylcholinesteraseHSP90 (Heat shock protein 90 chaperone complex)RELA (Nuclear Factor Kappa B Subunit p65)STAT1 (Signal transducer and activator of transcription protein 1)STAT3 (Signal Transducer and Activator of Transcription 3)ADAM10 (Disintegrin and metalloproteinase domain-containing protein 10)HSP90AA1 (Heat shock protein HSP90-alpha)HIF1A (Hypoxia-inducible factor 1-alpha)MEKNF-κBPPARG (Peroxisome proliferator-activated receptor gamma)PI3K (Phosphoinositide-3-kinase regulatory subunit 6)AKT (RAC-alpha serine/threonine-protein kinase)

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