TASIN in Oncology | Colorectal Cancer
We have discovered a new class of compounds, TASINs (Truncated APC Selective Inhibitors), that specifically kill cancer cells with the mutated or truncated APC (Adenomatous Polyposis Coli) gene without toxicity to normal cells.
This discovery could be key to catching colorectal cancer (CRC) at its earliest stage, since more than 80% of the ~1.8 million annual CRC cases first present with a mutation to the APC gene.
TASINs Cytotoxicity Overview:
TASIN disrupts intracellular cholesterol, which is critical for APC truncated cancer cell survival.
TASIN binds to emopamil binding protein (EBP), significantly reducing cholesterol levels within APC truncated cancer cells.
The cancer cells then become stressed.
Cellular defenses are disrupted.
(ER stress observed: JNK activation, increase in ROS, inhibition of Akt “pro-survival” cell signaling.)
Inhibition of EBP leads to a reduction of cholesterol levels within the cell resulting in ER stress and ultimately CRC cell death.
TASINs are orally bioavailable and have demonstrated to significantly reduce tumor size in preclinical APCtrunc mouse models.
Genetic Mouse Model:
TASIN-1 results in decreased number and size of polyps in the CPC;Apc genetic mouse model.
The CPC;Apc genetic mouse model is the most relevant colorectal cancer model to CRC in humans.
We’ve already seen outstanding activity in animal models leveraging synthetic lethality, without toxicity.
TASIN in Neurology | Multiple Sclerosis (MS)
- Myelin is an insulating, fatty sheath that protects nerve cells and speeds conduction of nerve impulses.
- Loss of myelin is the foundation of many neurological diseases, including multiple sclerosis (MS).
- Regeneration of myelin is mediated by oligodendrocyte progenitor cells (OPCs) which are stem cells in the central nervous system (CNS).
- Significant research underway to find new drugs that promote remyelination, but no such agents are on the market today.
TASIN Shows Promise in Demyelinating Disease:
- TASINs inhibition of EBP leads to accumulation of certain sterol intermediates in the cholesterol biosynthetic pathway, which then promotes oligodendrocyte formation.
- An experiment with oligodendrocyte progenitor cells (OPCs) treated for 72 hours with DMSO only, no drug (top right) indicates the lack of Oligodendrocyte myelin basic protein (MBP).
- The same experiment performed with TASIN-1 (bottom right) clearly shows the presence oligodendrocyte MBP+ via the abundance of immunostaining (green).
TASIN Oncology Program
- Potent, first-in-class small molecules licensed from University of Texas Southwestern – Medical Center.
- Selective for Truncated APC, an important and highly prevalent marker of colorectal cancer.
- Strong preclinical POC; currently selecting lead molecule.
- MOA via inhibition of EBP, intermediate enzyme in cholesterol biosynthesis.
- Represents a unique and large commercial opportunity.
- Another Pharma Co. with their EBP inhibitor drug, has initiated a Phase 1 trial in patients with brain cancer (Glioblastoma Multiforme, Gliomas)
TASIN Neurology Program
- Growing recognition of emopamil binding protein (EBP) as an important target in demyelinating diseases, such as multiple sclerosis.
- Clear interest from Big Pharma companies as EBP has been validated as a drugable target in MS.
- A publication in Nature showed that Barricade’s compounds restored myelin in vitro.
- Initial animal proof-of-concept study indicated presence of early biomarkers for remyelination.
- Barricade intends to rapidly advance a second-generation TASIN compound for this high-value indication.