Partnership seeks to develop KRAS degraders for cancer therapy

The Frederick National Laboratory for Cancer Research and biotech company Progenra, Inc., recently signed a contractor Cooperative Research and Development Agreement (cCRADA) to develop a novel therapy that could be capable of degrading KRAS.

Graphic representation of RAS gene

The human KRAS gene is one of the most elusive and potentially promising cancer therapy targets. KRAS mutations drive multiple cancers, including pancreatic, colorectal, and non-small-cell lung cancers.

On May 28, the FDA approved the first targeted therapy for tumors with a specific type of KRAS mutation. The FNL-Progenra study aims to affect a broader range of indications.

“The rapid approval of Amgen’s KRAS inhibitor Lumakras (sotorasib) by the FDA highlights the importance of KRAS-dependent cancer, which is considered the most undruggable target in cancer therapy,” said Tauseef R. Butt, Ph.D., CEO of Progenra, Inc. “However, the escape mutations of KRAS will remain a challenge and will limit the efficacy of the drug. This is the main reason for developing a new approach to degrade KRAS.”

“Taking into account drug resistance mechanisms, the most effective strategy to target KRAS-driven cancers is to specifically degrade KRAS. Such an approach would greatly benefit patients over a larger range of cancer indications than Lumakras,” explained Frantz Jean-Francois, Ph.D., FNL principal investigator in the partnership and team lead for the RAS degradation project, part of the RAS Initiative.

The concept for this collaboration began a little over a year ago, when Jean-Francois discovered that a compound had promising binding properties. These properties suggested that the compound would be a good KRAS handle for designing KRAS PROteolysis-TArgeting Chimeras (PROTACs) when linked to a ubiquitin ligase. Ubiquitin ligases are enzymes that participate in protein homeostasis.

“The cell has a built-in protein clearing process; its own way of disposing of proteins that are no longer useful,” said Jean-Francois. “PROTAC is a way of hijacking this normal process and targeting it toward proteins that you do not want. You can literally pick and choose proteins to eliminate.”

Collaborative approach

The FNL partnership to design the PROTACs will leverage Progenra’s experience using the ubiquitin proteasome system for drug discovery. The company is among the first to develop small molecule inhibitors of ubiquitin-specific proteases and to demonstrate that they have anticancer activity. Currently, the company is testing novel PROTAC molecules for their ability to selectively degrade KRAS.

“We are very excited to work with the RAS Initiative team, and we believe that their discovery and expertise coupled with our innovative PROTAC strategy will enable us to identify a clinical candidate,” said Butt.

The collaboration leverages both partners’ expertise. The FNL will coordinate the biology, biophysics, structural analysis, and mass spectrometry studies. Progenra will synthesize and provide the novel ubiquitin ligase ligand binder and lead the chemistry efforts. Progenra will also synthesize multiple PROTACs and identify and optimize the lead PROTACs for degrading KRAS.

The investigators will evaluate the PROTACs for antitumor activity in multiple cancer cell lines, but they are particularly interested in pancreatic cancer. KRAS mutations are the most prevalent oncogene mutation in pancreatic cancer, and the current five-year survival rate is just 10% for patients with pancreatic cancer—illustrating a substantial need for improved therapies.