Kymera Therapeutics, a clinical-stage biopharmaceutical company, has reported promising preclinical data on MDM2 degraders for the treatment of cancer. The company presented the data at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, as well as the 10th International MDM2 Workshop. Kymera’s MDM2 degraders have shown the ability to overcome limitations of small molecule inhibitors (SMIs) by rapidly inducing cell death in sensitive p53 wild-type cancer cell lines.
MDM2 is an important regulator of the tumor suppressor protein p53, which remains intact in approximately 50% of cancers. While SMIs have been developed to stabilize and upregulate p53 expression, they are limited by the feedback loop that increases MDM2 protein levels, thereby repressing p53. Kymera’s MDM2 degraders have demonstrated the potential to overcome this feedback loop and induce cell death in cancer cells, even with brief compound exposure. This suggests a potential for improved efficacy and safety compared to MDM2 SMIs.
One of Kymera’s lead MDM2 degraders, KT-253, has shown significant growth inhibition potency in vitro against p53 wild-type cancer cell lines compared to MDM2 SMI. In addition, it has demonstrated potent in vivo activity in models of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Furthermore, KT-253 has shown activity in combination with venetoclax, a drug used to treat certain cancers that are resistant to conventional therapies.
The data presented at the conferences also support MDM2 degradation as a promising therapeutic approach in Merkel cell carcinoma (MCC), a type of skin cancer. Kymera’s MDM2 degrader, KTX-049, has shown efficacy in vitro against p53 wild-type MCC cell lines with brief compound exposure. In mouse models, KT-253 has demonstrated tumor regressions with weekly and every three-week dosing, whereas an MDM2 SMI only showed modest tumor growth inhibition.
Jared Gollob, M.D., Chief Medical Officer at Kymera Therapeutics, emphasized that the results with MDM2 degraders demonstrate the company’s approach of targeting genes with strong genetic validation. He also highlighted the potential of MDM2 degradation to overcome the limitations of MDM2 SMIs and improve the stabilization of p53, leading to cancer cell death. Kymera is currently evaluating KT-253 in a Phase 1 trial for liquid and solid tumors and plans to share proof-of-mechanism data later this year.
Kymera Therapeutics is a biopharmaceutical company that specializes in targeted protein degradation. Its Pegasus platform aims to develop small molecule programs that degrade disease-causing proteins. The company’s pipeline includes programs targeting various immune-inflammatory diseases, hematologic malignancies, and solid tumors.
In conclusion, Kymera Therapeutics’ preclinical data on MDM2 degraders for cancer treatment show promising potential in overcoming the limitations of current therapies. The company’s approach of targeted protein degradation presents an opportunity for improved efficacy and safety in the treatment of p53 wild-type liquid and solid tumors. Kymera’s ongoing Phase 1 trial of KT-253 will provide further insights into the therapeutic potential of MDM2 degraders.
