Ubiquitin-proteasome pathway. The proteasome is an enzyme complex within the cell responsible for breaking down proteins that have been marked for removal by the attachment of a tag called ubiquitin. The ubiquitin-proteasome pathway plays an essential role in regulating the concentration of specific proteins inside the cell, thereby maintaining 'homeostasis', the natural tendency of the cell to remain stable. Inhibition of the proteasome prevents this targeted degradation of proteins, which can affect multiple signaling cascades within the cell. This disruption of normal stability-control mechanisms can lead to cell death. Experiments have demonstrated that proteasome inhibition causes the death of a variety of cancer cell types in vitro, and a delay in tumor growth in animal models.

Leukocyte activation and migration. Leukocytes, or white blood cells, include a number of specialized cell types that play important roles in inflammatory processes. Their role is to repair and remodel damaged tissue and to dispose of foreign substances. They are recruited to sites where they are needed by molecular signals released by damaged tissue, for example, and by other leukocytes that have already been recruited. In certain circumstances, the activation and recruitment of leukocytes go beyond what is strictly needed, causing inflammatory diseases such as rheumatoid arthritis and asthma. Additionally, diseases such as atherosclerosis may be medicated by targeting leukocyte trafficking. Millennium has developed several drug candidates to control inflammation that are in or close to being in clinical trials. These include MLN02 and MLN1202, being developed as potential treatments for patients with, respectively, inflammatory bowel disease and rheumatoid arthritis and other chronic inflammatory diseases.

Cell-cycle control. New cells in the body are created by the division of existing cells. A cell which is about to divide goes through an orderly series of steps to duplicate essential components that are then shared between the two new "daughter" cells. Each successive generation of cells goes through the same series of steps, which is therefore known as the "cell cycle". In tumor cells, however, control of this cell cycle breaks down, allowing the cells to divide repeatedly in circumstances under which normal cells would stop. Drugs that restore cell-cycle control should prevent uncontrolled proliferation of tumor cells. Such drugs may also be useful in restraining the proliferation of various white blood cells that occurs during the inflammatory responses that underlie a number of important diseases.

Kinase-mediated signaling. The cell uses a variety of mechanisms to control and coordinate the activities of the many different proteins that conduct its business. One of the most common mechanisms is the addition of phosphate groups at specific sites on individual proteins, leading to an increase or decrease in the activity of those proteins. The enzymes that speed up (catalyze) this addition of phosphate groups have a major influence on the overall behavior of the cell. These enzymes are called kinases. One of the important roles kinases play is to relay signals that come from outside the cell so as to generate appropriate responses. Sometimes, however, kinases behave as though a signal has been received even when it has not. An example of this inappropriate signal processing occurs in tumors, where a kinase may keep stimulating cells to divide even when there are no external signals that they should continue to divide, resulting in uncontrolled growth of the tumor — the hallmark of cancer. For this reason, blocking the activity of inappropriately activated kinases is a promising approach for cancer treatment. The Millennium drug candidate MLN518 has been designed to block one such faulty kinase that appears to play a role in acute myeloid leukemia (AML).