Serine palmitoyltransferase (SPT) is a key enzyme of sphingolipid metabolism. And it belongs to a family of pyridoxal 5′-phosphate-dependent alpha-oxoamine synthases. Sphingolipids are one of the major membrane lipids in mammalian cells. They play an important role in a wide spectrum of cellular functions such as cell growth, adhesion, migration, and death. Defects in sphingolipid metabolism play an important role in cancers and neurodegenerative diseases. The first step in the biosynthesis of sphingolipids is the condensation of serine and palmitoyl CoA, a reaction catalyzed by SPT. Therefore, one key enzyme of the sphingolipid biogenesis is SPT. In addition to palmitoyl-CoA, it can also use other acyl-CoAs as substrates. SPT is an essential protein for the survival of mammals.

In humans, mutations in SPT are linked to hereditary sensory neuropathy type 1 (HSAN1) and early onset amyotrophic lateral sclerosis (ALS). Meanwhile, SPT is also a target for cancer and diabetes therapy. Mammalian SPT is a heterodimer of 53-kDa LCB1 and 63-kDa LCB2 subunits, both of which can bind to the endoplasmic reticulum (ER). Furthermore, Potent inhibitors of SPT structurally resemble an intermediate in a probable multistep reaction mechanism for SPT. Although SPT is a housekeeping enzyme, its activity is regulated transcriptionally and post-transcriptionally. And its up-regulation plays a role in stress-induced apoptosis.

ARN14494 is a potent and selective SPT inhibitor.

ARN14494 protects neurons from β-amyloid 1-42-induced neurotoxicity through a variety of mechanisms, including anti-oxidation, anti-apoptosis, and anti-inflammation. In mouse primary astrocytes, ARN14494 inhibits SPT activity in a concentration-dependent manner. What’s more, ARN14494 decreases ceramide and dihydroceramide levels in primary cortical astrocytes treated with Aβ1-42. ARN14494 inhibits oligomeric Aβ-induced production of pro-inflammatory molecules including NO, TNF-α, IL1β, TGF1β, and pro-inflammatory enzymes INOS and COX-2 in cultures of primary astrocytes. Besides, ARN14494 reduces Aβ neurotoxicity and caspase-3 activation treated with astrocyte-conditioned medium in cultures of cortical neurons. Therefore, ARN14494 affects the CNS in terms of anti-inflammation and neuroprotection.

All in all, ARN14494, a potent and selective SPT inhibitor, has the potential for Alzheimer’s disease research.


[1] Wang Y, et, al. Nat Struct Mol Biol. 2021 Mar;28(3):240-248.

[2] Vita TD, et, al. ACS Chem Neurosci. 2019 Mar 20;10(3):1627-1635.