Frontier Medicines Announces Oral Presentation on Dual-Acting Inhibitors of the Active and Inactive Forms of KRAS G12C at the American Association for Cancer Research (AACR) Annual Meeting

March 9, 2022

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 KRASG12C 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 KRASG12C, 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 KRASG12C, 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%) KRASG12C engagement with our dual-acting inhibitors, which resulted in tumor regression. Therefore, we believe that a drug that inhibits both forms of KRASG12C 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 KRASG12C 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 KRASG12C 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 KRASG12C, 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 KRASG12C were equally effective in the G12C/A59G and parental G12C cell lines. 

Presentation Information


Discovery of Novel Dual-Acting KRASG12C Inhibitors that Target Both the Active and Inactive Forms of the Protein

Abstract Number:


Session Title:

Targeting the RAS Oncogene

Session Date and Time:

April 12, 2022, 2:30pm - 4:30pm CT

Presentation Time and Location:

4:05-4:20pm CT, Room 353-355

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 KRASG12C and is distinct in that it targets direct inhibition of both the activated and inactive forms of KRASG12C. 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 and follow us on LinkedIn and Twitter.