The extracellular signal-regulated kinase (ERK) pathway is crucial to cancer cell immune evasion, proliferation, and survival and plays a pivotal role in cancer therapy resistance. Thus, inhibiting it is profoundly important for controlling tumor growth and progression. Activating mutations in the oncogene KRAS, which activates ERK, are one of cancer's most frequently occurring driver mutations. Although selective inhibitors of one form of oncogenic KRAS G12C (e.g., Sotorasib and Adagrasib) are in clinical use, over half the patients do not respond, and median progression-free survival is only about six months. An alternative approach is to target downstream effector kinases, such as ERK. We...

Read More

The extracellular signal-regulated kinase (ERK) pathway is crucial to cancer cell immune evasion, proliferation, and survival and plays a pivotal role in cancer therapy resistance. Thus, inhibiting it is profoundly important for controlling tumor growth and progression. Activating mutations in the oncogene KRAS, which activates ERK, are one of cancer's most frequently occurring driver mutations. Although selective inhibitors of one form of oncogenic KRAS G12C (e.g., Sotorasib and Adagrasib) are in clinical use, over half the patients do not respond, and median progression-free survival is only about six months. An alternative approach is to target downstream effector kinases, such as ERK. We have discovered a series of compounds that efficiently entrap ERK in vivo within unique inactivated complexes. These complexes inhibit ERK signaling and abrogate ERK-protein interactions to suppress important compensatory signals. The long-term goal is to develop therapeutically useful ERK inhibitors for clinically treating malignancies. The overall objectives of this application are to create a novel class of inhibitors that entraps ERK into an inactive complex in cancer cells. The central hypothesis is that inhibitors that entrap ERK can be developed to possess suitable potency to cause tumor regression in models predictive of clinical efficacy. The project's rationale is that creating a new chemical strategy to inhibit ERK and determining its preclinical therapeutic efficacy and associated mechanisms will likely offer a robust scientific framework for developing new cancer therapeutic approaches.

Read Less