Calithera’s ongoing research efforts are focused on discovering additional product candidates against novel tumor metabolism and immunology targets.

Tumor metabolism and tumor immunology have emerged as promising new fields for cancer drug discovery, and recent clinical successes with therapeutic agents in each field have demonstrated the potential to create fundamentally new therapies for cancer patients. We have accumulated significant experience and understanding of tumor metabolism and tumor immunology and are applying our medicinal chemistry capabilities to identify small molecules that exploit these pathways. To date, we have utilized this expertise to internally discover CB-839, our first-in-class oncology product candidate that is now in clinical testing. We plan to continue to leverage our expertise to discover and develop additional product candidates advance those product candidates through clinical testing, and, if approved, ultimately commercialize meaningful therapies for patients with cancer.

Tumor Metabolism

Many types of cancer cells develop a unique dependence on specific metabolic pathways upon which normal cells are not reliant. The primary goal of drugs targeting tumor metabolism pathways is to take advantage of cancer-specific nutrient dependencies to block cancer growth.

The field of tumor metabolism seeks to exploit the unique ways in which cancer cells take up and utilize nutrients in order to grow and survive. It is now recognized that cancer cells rely on certain metabolic processes, or pathways, to a much greater extent than normal cells. Accordingly, when these metabolic pathways are blocked, cancer cells are essentially starved of critical nutrients and stop growing or die, whereas normal cells are largely unaffected. Changes in cellular metabolism are remarkably consistent across many tumor types, yet fundamentally different from normal cells, providing the potential to develop broadly applicable agents that target these altered pathways, but have less toxicity than standard cytotoxic agents.

Our lead product candidate in tumor metabolism, CB-839, takes advantage of the pronounced dependency many cancers have on the nutrient glutamine for growth and survival. CB-839 inhibits glutaminase, an enzyme required by cancer cells to utilize glutamine effectively.

Tumor Immunology

The field of tumor immunology seeks to activate the body’s own immune system to attack and kill cancer cells. Genetically diverse tumor types have developed mechanisms to escape destruction by the body’s immune system.

One key mechanism is through suppression of cytotoxic T cells that would otherwise attack and kill the cancer cells. Arginine is an amino acid that is fundamental to the function of cytotoxic T cells. Without arginine, tumor- specific cytotoxic T cells fail to express a functional T cell receptor on their surface and as a result are unable to activate, proliferate, or mount an effective anti-tumor response.

We believe that inhibitors of arginase can promote an anti-tumor immune response by restoring arginine levels, thereby allowing activation of the body’s cancer-fighting immune cells.

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