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Destroying Mutant Proteins as an Emerging Cancer Treatment: A Q&A with a New LLS TAP Partner

By Andrea Greif |

Kymera Therapeutics is a biotech company pioneering an emerging approach to cancer therapy called “targeted protein degradation.” Whereas most targeted therapies inhibit or inactivate the proteins or genes that drive the cancer, targeted protein degradation harnesses the body’s natural system of ridding itself of unwanted, ‘old’ or ‘broken’ components of cells. In March 2020, LLS made a strategic investment in Kymera’s work to treat blood-based cancers through our Therapy Acceleration Program, our venture philanthropy model through which we partner with biotech companies to advance promising therapies. Here, Kymera’s Chief Medical Officer Jared Gollob, M.D., discusses some of its lead programs with LLS:

Q. What is targeted protein degradation?

A. Protein degradation is a natural mechanism or process by which our body’s cellular machinery breaks down or degrades unwanted proteins. Scientists first uncovered this mechanism in the 1980s, and Drs. Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize for the discovery in 2004. Targeted protein degradation (TPD) is a new therapeutic modality that uses a small molecule “degrader” drug to chemically co-opt this innate cellular process toward specific disease-causing proteins.

Q. Why is TPD a promising new treatment approach for cancer?

A. Cancer is often caused by mutations or the over-production of specific proteins in the body. While conventional small molecule inhibitor drugs and antibody therapeutics have had a tremendous impact on the treatment of diseases, including cancer, it is estimated these traditional approaches have only be able to effectively drug approximately 20% of the full human genome to date. We believe TPD represents an opportunity to target a wide array of proteins that previously have been considered undruggable. This is very important in blood cancer, because we already know that many of the key proteins that drive these cancers have not been druggable with conventional approaches. Furthermore, protein degrader therapies are small molecule drugs that can be administered orally, or in pill-form, making them more broadly accessible for patients.

Q. LLS has invested in Kymera as part of our TAP program. What does this partnership mean for Kymera?

A. The Leukemia & Lymphoma Society has developed a reputation for investing in the most promising new therapeutic approaches, helping to deliver breakthrough therapies for patients. We are honored and delighted to be partnering with LLS to advance what we see as truly innovative therapeutics with the potential to transform cancer treatment for patients. This collaboration will further our research efforts and ensure patients have access to clinical studies and the latest information on our approach and medicines.

Q. Can you elaborate further on Kymera’s approach and relevant therapies in development?

A. Kymera is working at the forefront of TPD to invent new medicines for difficult-to-treat cancers, as well as for immune-inflammatory diseases. Our proprietary Pegasus drug discovery platform enables us to design potent, highly selective molecules that utilize the body’s natural protein degradation pathway, involving so-called “E3 ligases” (enzymes needed to tag a protein for disposal), to target and degrade disease-causing proteins. Pegasus combines our broad understanding of the localization and expression levels of the hundreds of E3 ligases in the human body with our proprietary E3 Ligase Binders Toolbox, as well as our chemistry, biology, and computational capabilities to develop protein degraders that address significant, unmet medical needs.

At this year’s American Association of Cancer Research (AACR) meeting, which took place virtually on June 22-24, we presented the first preclinical data on our novel IRAKIMiD degraders, showing robust antitumor activity in lymphomas with the MYD88-mutation, which constitute approximately one quarter of all diffuse large B-cell lymphomas (DLBCL). Also, at AACR, we shared new findings from our highly selective STAT3 degrader program – demonstrating potent antitumor activity in a solid tumor models not responsive to approved immunotherapies. This complements our previous data showing our STAT3 degraders are capable of driving tumor regression in animal models of STAT3-dependent blood-based cancers.

Q. What can we expect to see from Kymera in the next year?

A. Kymera is rapidly advancing our IRAKIMiD and STAT3 programs toward the clinic with plans to initiate Phase 1 studies in the second half of 2021. We will also continue to expand our pipeline of protein degrader therapies to treat additional blood-based and tissue-based cancers with high unmet medical need. We look forward to our continued partnership with LLS and to advancing new, potentially breakthrough medicines for patients.