SM-88 Overview

SM-88 is a novel oral monotherapy that is used in investigational studies with three other drugs: methoxsalen, phenytoin, and sirolimus (hereafter, referred to as SM-88 used with MPS). SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS. Tyrosine is a non-essential amino acid that is readily consumed by cancer cells but has shown minimal uptake by normal healthy cells. SM-88 is designed to be absorbed by the cancer cell as if it were a functional tyrosine, but after uptake, interrupt the processes of protein synthesis. Disrupting the protein synthesis also impedes key defenses of the cancer cell, making it vulnerable to oxidative stress and apoptosis.

The key target we aim to disrupt within the cancer cell is mucin, specifically mucin 1, produced by the MUC1 oncogene. Mucin is highly overexpressed by most cancer cells and acts as a protective layer on the outside of each cancer cell, offering multiple defenses to the harsh tumor microenvironment and shielding it from the immune system.

The internal environment of cancer cells is also harsh, with elevated levels of free radicals or reactive oxygen species (ROS) created from the altered metabolism that cancers utilize (aerobic glycolysis). MUC1 has also been shown to be important in balancing the elevated ROS by triggering the upregulation of key antioxidant defenses of the cell and preventing cancer from triggering its own death (apoptosis).

Overall, SM-88’s disruption of the cancer cell’s protein synthesis further destabilizes an already vulnerable cell with a goal of triggering cell death and potentially immune recognition of the cancer cell. 

There are three additional components to SM-88 used with MPS: sirolimus, phenytoin, and methoxsalen used at sub-therapeutic levels to alter the physiology of the patient or their tumor in order to complement and augment the activity of SM-88. Each agent is FDA approved, generic, and has years of research behind the physiological mechanism for which it is employed in our therapy.

  • Rapamycin (mTOR inhibitor approved for transplant rejection)
    The purpose is to alter cancer to a nutrient-seeking state and drive increased uptake of our dysfunctional tyrosine.
  • Phenytoin (P450 3A4 inducer approved for epilepsy)
    This drug is recognized to trigger steady liver release of reactive lipids that can accumulate in the tumor microenvironment. Cancer cells readily absorb lipids and this further attenuate the ROS imbalance inside these cell.
  • Methoxsalen (inducer of melanocyte production approved for treatment of severe psoriasis)
    Melanocytes produce melanin which acts as an electron donor. We believe having a patient in an elevated catalytic state could promote electron transfer and drive the oxidative reactions occurring in the tumor cell.

We believe the broad disruption caused by SM-88, together with a combinational approach of repurposed drugs with well documented properties to alter the tumor biology or microenvironment has merits compared to current targeted therapy approaches that ultimately lead to resistance.