TASIN in Oncology | APCmut 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.

APC mutated cells (APCmut) have impaired capability to regulate cholesterol production & importation thus become vulnerable to drugs that inhibit Emopamil Binding Protein (EBP) resulting in their programmed cell death.

This discovery could be key to catching colorectal cancer (CRC) at its earliest stage, since more than 80% of the ~1.9 million annual CRC cases first present with the APCmut gene.

TASIN MOA | Cytotoxicity Overview:

TASIN disrupts intracellular cholesterol, which is critical for APC truncated (APCmut) cancer cell survival.

1

TASIN binds to emopamil binding protein (EBP), significantly reducing cholesterol levels within APCmut cancer cells.

2

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.)

3

End Result: Programmed colorectal cancer cell death (apoptosis)

Inhibition of EBP leads to a reduction of cholesterol levels within the APCmut cell resulting in ER stress and ultimately CRC cell death.

(S)-TASIN-15 is orally bioavailable and has demonstrated to significantly reduce tumor size in preclinical APCmut mouse models.

TASIN Efficacy in vivo

Genetic Mouse Model of Colorectal Cancer:

TASIN drugs result in decreased number and size of tumors in a genetically engineered mouse model of CRC.

The CPC;Apc genetic mouse model1 is the most relevant colorectal cancer model to CRC in humans2.

Outstanding activity has been demonstrated in CRC animal models leveraging synthetic lethality with TASIN analogs as well as with our lead clinical candidate, (S)-TASIN-15. 

1. CDX2P-NLS Cre;Apc+/loxP (CPC;Apc)
2. The human gene, CDX2, contains key elements for colorectal tumor formation.

TASIN in Neurology | Multiple Sclerosis (MS)

Overview:

  • 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).

Overview of Therapeutic Programs

TASIN Oncology Program

Colorectal Cancer

  • Potent, first-in-class small molecules licensed from University of Texas Southwestern – Medical Center.
  • Selective for APCmut, an important and highly prevalent marker of colorectal cancer.
  • Strong preclinical POC
  • Clinical candidate declared, (S)-TASIN-15.
  • MOA via inhibition of EBP, intermediate enzyme in cholesterol biosynthesis.
  • Represents a unique and large commercial opportunity.
  • Another Pharma Co’s. EBP inhibitor drug is currently under investigation in a Phase 1 trial for patients with brain cancer (Glioblastoma Multiforme, Gliomas)

TASIN Neurology Program

Multiple Sclerosis

  • 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.

Moving Forward:

  • Our clinical candidate, (S)-TASIN-15, is protected by global patents: Composition of Matter & Method of Use.
  • Barricade plans to submit its first IND during 1H2024 followed by initiation of the Phase I clinical trial in advanced APCmut CRC patients.
  • Human POC in colorectal cancer is projected in 2024-2025.
  • Concurrently, we will advance a second-generation TASIN molecule for neurology applications, with potential for rapid human POC.