HPA-12 

HPA-12 is a blood-brain barrier-permeable small-molecule inhibitor of ceramide transfer protein (CERT) with four stereoisomers (the (1R,3R)-stereoisomer exhibits the highest activity). HPA-12 blocks the transport of ceramide from the endoplasmic reticulum to the Golgi apparatus by binding to the START domain of CERT, leading to intracellular ceramide accumulation and inhibition of sphingomyelin (SM) synthesis. HPA-12 induces endoplasmic reticulum stress via the GRP78/ATF6/CHOP axis and activates mitochondrial autophagy, thereby inhibiting cell growth and inducing apoptosis. In in vivo experiments, HPA-12 significantly reduces the leukemia burden and splenomegaly in mouse models of acute myeloid leukemia (AML) and prolongs survival. HPA-12 is applicable for the research of lipid metabolism in acute myeloid leukemia and Alzheimer's disease^[1][2][3].

HPA-12 (60-100 μM; 48 h) reduces the viability and proliferation of FLT3^ITD+ MV4-11 and Molm13 acute myeloid leukemia (AML) cell lines in a dose-dependent manner, but exerts no effect on FLT3^-WT AML cell lines after 48 h of treatment^[1].
Treatment with HPA-12 (100 μM; 48 h) induces apoptosis in FLT3^ITD+-type Molm13 AML cells^[1].
HPA-12 (2.5 μM; 30 min) inhibits CERT-mediated intracellular trafficking of fluorescent ceramide analogs in HeLa cells and prevents the accumulation of such analogs in the perinuclear Golgi region^[2].
HPA-12 (0.1-2.5 μM; 2-5 h) potently and concentration-dependently inhibits de novo SM synthesis in CHO cells, exerts weak effects on Cer and GlcCer synthesis, and has no impact on the synthesis of phosphatidylethanolamine or phosphatidylserine^[3].
HPA-12 (2.5 μM; 48 h) reduces the content of SM by approximately 30% in CHO cells, while increasing the content of glycosphingolipids, without altering the content of total phospholipids or Cer, nor inhibiting the synthesis of PC (1 μM HPA-12; 4 h)^[3].
HPA-12 (20 μM; 10 min-1 h) is not an in vitro inhibitor of SM synthase or other key enzymes involved in de novo sphingolipid synthesis^[3].
(1R,3R)-HPA-12 (1 μM; 15 min pre-treatment + 30 min exposure) primarily inhibits the ATP-dependent pathway of ceramide transport from the endoplasmic reticulum to sphingomyelin (SM) synthesis sites in CHO cells^[3].
(1R,3R)-HPA-12 (2.5 μM; 0-120 min) does not inhibit the trafficking of GPI-anchored or transmembrane glycoproteins from the endoplasmic reticulum (ER) to the Golgi apparatus in CHO cells^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Monotherapy with HPA-12 (4 mg/kg; s.c.; 5 days on followed by 2 days off, 2 cycles) reduces AML burden in xenograft mice, and exhibits a synergistic effect when combined with Crenolanib (HY-13223) (15 mg/kg; i.p.; 5 days on followed by 2 days off, 2 cycles), while reducing leukemia burden without causing significant body weight loss in mice^[1].
[¹⁸F]HPA-12 (1.5 MBq; i.v.; single administration), a radiolabeled form of HPA-12, crosses the blood-brain barrier and accumulates in the brain of wild-type mice. Its uptake exhibits brain region dependence, with an average SUV of approximately 0.3 at 1 h post-injection^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

363.53

C₂₂H₃₇NO₃

383418-30-2

Solid

White to off-white

CCCCCCCCCCCC(N[C@@H](CO)C[C@H](O)C1=CC=CC=C1)=O

Room temperature in continental US; may vary elsewhere.

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

• [1]. Sun X, et al. Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis. Nat Commun. 2025;16(1):1358. Published 2025 Feb 4.  [Content Brief]

  [2]. Crivelli SM, et al. Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. J Alzheimers Dis. 2017;60(3):783-794.  [Content Brief]

  [3]. Yasuda S, et al. A novel inhibitor of ceramide trafficking from the endoplasmic reticulum to the site of sphingomyelin synthesis. J Biol Chem. 2001;276(47):43994-44002.  [Content Brief]