SOUTH SAN FRANCISCO, Calif. -- Frontier Medicines Corporation, a precision medicine company seeking to unlock the proteome to advance breakthrough therapies against otherwise undruggable disease-causing targets, today announced the company will have an oral presentation entitled, “Discovery of Novel Dual-Acting KRAS^G12C Inhibitors that Target Both the Active and Inactive Forms of the Protein” at the American Association for Cancer Research (AACR) Annual Meeting taking place April 8-13, 2022 in New Orleans, LA.

“KRAS is a prominent cancer-driving gene, and the recent availability of drugs that target mutated KRAS has opened up an important new therapeutic option for patients,” said Chris Varma, Ph.D., Frontier’s co-founder, chairman, and CEO. “However, current inhibitors bind only to the inactive (GDP-bound) form of KRAS^G12C, and a majority of patients on treatment fail to achieve a clinical response or relapse. Our preclinical data demonstrate that by targeting both the active (GTP-bound) and inactive (GDP-bound) states of KRAS^G12C, our compounds have potent cellular activity in cancer models where single-acting KRAS inhibitors do not. Additionally, in an in-vivo model of pancreatic cancer, we were able to demonstrate rapid and near-complete (>90%) KRAS^G12C engagement with our dual-acting inhibitors, which resulted in tumor regression. Therefore, we believe that a drug that inhibits both forms of KRAS^G12C will have the potential to drive broader and more durable clinical responses.”

The study was conducted in preclinical models that are both sensitive (NCI-H358 and MIA PaCa-2) and resistant (NCI-H2122) to first-generation KRAS^G12C inhibitors (adagrasib and sotorasib). While first-generation inhibitors were less effective in the NCI-H2122 cell line model, dual-acting inhibitors of GTP- and GDP-bound KRAS^G12C elicited rapid inhibition of pERK in < 1 hour, with sustained inhibition of MAPK signaling through 48 hours. To model resistance to first-generation inhibitors, an A59G mutation was introduced into KRAS^G12C, abrogating GTPase activity. This decreased the activity of both adagrasib and sotorasib in tumor cell viability assays by more than an order of magnitude, whereas dual-acting inhibitors of GTP- and GDP-bound KRAS^G12C were equally effective in the G12C/A59G and parental G12C cell lines. 

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About Frontier Medicines

Frontier Medicines is a precision medicine company that has pioneered a powerful discovery and development platform designed to generate medicines against disease-causing proteins previously considered undruggable. The company is deploying its technologies in chemoproteomics, covalent drug discovery, and machine learning to potentially develop groundbreaking medicines for genetically-defined patient populations, starting in cancer. Frontier is advancing its wholly-owned pipeline of precision medicines against the most important drivers of cancer. The company’s lead program is focused on KRAS^G12C and is distinct in that it targets direct inhibition of both the activated and inactive forms of KRAS^G12C. This KRAS mutation is found most prevalently in patients with non-small cell lung, colorectal, and pancreatic cancers. For more information on how Frontier is boldly advancing science to defeat disease, visit www.frontiermeds.com and follow us on LinkedIn and Twitter.