Thursday, October 29, 2015

Drugs in Clinical Pipeline: ABTL0812

ABTL0812 [sodium 2-hydroxylinoleate] is an orally available lipid analogue that hits two clinically validated targets: mTOR and DHFR.  Both these clinically validated targets are responsible for the cytotoxic effect of ABTL0812: mTOR (mammalian target of rapamycin), as shown by the dramatic reduction in S6 phosphorylation, and dihydrofolate reductase (DHFR), as shown by its reduced expression, resulting in autophagic cell death. Moreover, the compound's cellular potency increases with incubation time, and it has a long lasting cytotoxic effect after removing the compound from the incubation medium. This multi-target property increases antitumor efficacy and reduces drug resistance. In addition, preliminary in vivo results indicate that the potential therapeutic margin will be high [1].

ABTL0812 has cytotoxic effect on a wide range of human tumor cell lines, including those which have become resistant to standard therapy. ABTL0812 molecular targets were identified by in silico analysis, comparing ABTL0812 chemical structure against a database including more than one million receptor-ligand interaction data. Functional relevance of the targets was confirmed biochemically and pharmacologically. ABTL0812 mechanism of action was established using human lung and pancreatic tumor cells, MEF KO cells, as well as tumor xenografts.

In silico screening showed that ABTL0812 binds four targets which regulate tumor progression through Akt/mTOR axis. Two of them are the transcription factors PPARα and PPARγ (Peroxisome-Proliferator Activating Receptors). In lung and pancreatic tumor cells ABTL0812 activated PPARα/γ-dependent gene transcription, while pharmacological inhibition with PPARα/γ antagonists impaired ABTL0812 cytotoxic effect. Interestingly, ABTL0812 induced transcription of the endogenous Akt inhibitor TRIB3 (tribbles homologue 3) through PPARα/γ activation. TRIB3 is a pseudokinase that inhibits Akt by direct binding and preventing its phosphorylation by mTORC2 complex. According to this, ABTL0812-induced TRIB3 overexpression resulted in inhibition of Akt phosphorylation, impaired phosphorylation of the Akt substrates TSC2 and PRAS40 and mTORC1 inhibition (pS6), which in turn promoted autophagy-mediated tumor cell death. MEF TRIB3-/- cells were resistant to ABTL0812-induced cell death, indicating that TRIB3 mediates ABTL0812 cytotoxicity. Finally, Akt inhibition was observed in human lung and pancreatic tumor xenograft models treated with ABTL0812 and in human platelets incubated with ABTL0812. This supported the rational for using Akt phosphorylation as a pharmacodynamic biomarker to monitor activity of ABTL0812 in patients included in the Clinical Trial [2].

ABTL0812 was originally developed by Lipopharma and has been licensed to Ability Pharmaceuticals. In Aug 2015 Ability Pharmaceuticals, received orphan drug designation from the U.S. FDA for ABTL0812 in the treatment of neuroblastoma.  The European Medicines Agency (EMA) granted ABTL0812 orphan drug status in April 2015 for the same indication. Neuroblastoma is a rare type of cancer originated from nerve cells and is the most common solid tumor outside the brain in children.  The prognosis for high-risk neuroblastoma cases is poor with no effective treatment.

Common Name: ABTL0812
Synonyms: ABTL0812; ABTL 0812; ABTL-0812
IUPAC Name:  Sodium 2-hydroxylinoleate
CAS Number: -
Mechanism of Action: Kinase Inhibitor; MTOR Inhibitor; AKT Inhibitor; DHFR Inhibitor; Dihydrofolate Reductase Inhibitor
Indication: Various Cancers; Treatment of Neuroblastoma
Development Stage: Phase I
Company: Lipopharma/Ability Pharma

1. Alfon, J.; et. al. Abstract 922: ABTL0812: A new drug class with oral antitumor action inhibiting mTOR activity and DHFR expression. Cancer Res 2012, 72, 922.
2. Gomez-Ferreria, M.; et. al. Abstract 672: ABTL0812, a new antitumor drug that inhibits the axis Akt/mTOR through a novel mechanism of action. Cancer Res 2015, 75, 672.
3. Escriba, R. P. V.; et. al. Use of polyunsaturated fatty acid derivatives as medicaments WO2010106211A1