The synthesis of proteins is a normal part of every cell's activity that is essential for life. Proteins are linear chains of building blocks known as amino acids. In order to function normally in a cell, proteins must fold into particular three dimensional shapes. During stressful conditions (e.g. during certain disease states), proteins can fold into inappropriate shapes that result in aggregation of proteins, which can be toxic to the cell. As an example, it is believed that certain genetic cases of ALS are caused by misfolding and aggregation of mutated forms of the superoxide dismutase 1 (SOD1) protein, leading to the death of motor neurons that cause ALS.

In addition to genetic causes of protein misfolding, it is believed that environmental insults, either physical (heat, pressure, radiation) or chemical (heavy metals, arsenate, toxins), also cause proteins to misfold into toxic shapes. To protect itself from damage, the cell activates the "cellular stress" response (also referred to as the "unfolded protein response"). One of the most important components of the stress response that allows the cell to survive such stress is the production of "molecular chaperone" proteins.

Molecular chaperones detect proteins that are misfolded, and have the ability to refold those proteins into the appropriate, non-toxic shape. Additionally, if the protein is so badly misfolded that it cannot be repaired, the molecular chaperones can also recruit other proteins that have the ability to "tag" the toxic protein for destruction by the cell. This tag, called ubiquitin, directs the misfolded protein to a cellular apparatus known as the proteasome, whose function is to degrade the toxic protein into its constituent amino acids for recycling.

Activation of molecular chaperone expression by the stress response can be an important mechanism for cellular survival during certain acute stresses. For instance, prior induction of the stress response can protect tissue culture cells from heat-induced cell death. However, it appears that the constant stress that occurs as a result of chronic disease dulls the stress response and erodes the effectiveness of the mechanism. For instance, although the stress response is slightly induced in the motor neurons of an ALS mouse model, the level of expression is apparently insufficient to repair the damage and the mice still die from the disease.

CytRx believes that by boosting the stress response to higher levels, the progression of chronic diseases like ALS can be slowed, halted or reversed. In test tube experiments, mammalian cells engineered to have increased amounts of molecular chaperones are protected against a variety of otherwise lethal stresses. In animal studies, mice that have been genetically engineered to have increased amounts of a molecular chaperone had improved heart function after an experimental heart attack. Increased molecular chaperone amounts also significantly increased the lifespan of mice with diseases similar to ALS, such as Spinal and Bulbar Muscular Atrophy, Parkinson's disease, and Huntington's disease. CytRx believes that these studies give scientifically accepted support for the development of drug candidates that are capable of boosting the stress response through molecular chaperone amplification.

CytRx has several orally available drug candidates whose mechanism of action is believed to be the "co-induction" of the stress response, meaning that they do not seem to activate the stress response by themselves, but instead they amplify the production of molecular chaperone proteins that are already activated by disease-induced cellular stress. These drug candidates thus may selectively amplify molecular chaperone proteins specifically in diseased tissue, which would minimize potential drug side-effects. The amplification of this fundamental protective mechanism may have powerful therapeutic and prophylactic properties, with the potential for an extremely broad field of medical therapeutic utility.