Chemoprotection and ALRN-6924

We are developing ALRN-6924 as a novel chemoprotective medicine to treat and protect healthy cells in patients with cancer that harbors p53-mutations to reduce or eliminate chemotherapy-induced side effects.

Role of P53

The p53 protein plays a central role in the mechanisms that defend the human body from cancer, including regulation of cell division and progression through the cell cycle, programmed death of cancerous cells (or “apoptosis”), and inducing the immune system to respond against cancer cells.

When DNA damage is detected in a cell (for example, following UV radiation), p53 activates genes that interrupt the cell cycle to ensure that damaged cells do not grow and propagate uncontrollably, leading to cancer. Functional p53 is therefore critical to human health, earning it the title of  “the guardian of the genome.” When p53 itself is mutated or pathologically inhibited by its natural regulators, cells grow uncontrollably and may eventually form a cancerous tumor. Approximately half of all cancer patients at initial diagnosis have cancers that circumvent the p53 mechanism by deactivating mutations in p53 itself, commonly referred to as mutant p53.

MDM2 is the primary regulator of p53, which acts by shuttling p53 out of the nucleus and targeting it for degradation. MDMX, which generally acts to sequester p53, is most abundantly expressed in normal bone marrow cells.  In the event of DNA damage, these two suppressor proteins detach from p53 so that it is activated to respond to DNA damage.

Low levels of p53 induce cell cycle arrest, which is the basis for the cell to repair DNA damage.  High levels of p53 can, under certain circumstances, trigger apoptosis, a form of programmed cell death.  This is one of the body’s natural defense mechanisms against cancer and for dealing with DNA damage.