Three investigational RAS-targeting drugs co-developed over the last six years by RAS Initiative scientists at the Frederick National Laboratory for Cancer Research (FNL) reached the clinic last year and are now being tested in humans.

Each compound has a different mechanism of action to target RAS-related cancers and was developed in partnership with BridgeBio Oncology Therapeutics (BBOT) and Lawrence Livermore National Laboratory (LLNL).

BBO-8520

  • An investigational treatment for adult patients with KRASG12C-mutated metastatic non-small cell lung cancer and granted Fast Track designation by the U.S. Food and Drug Administration.
  • The drug targets KRASG12C, the most common KRAS variant in lung cancer. Laboratory assays conducted by the team led by FNL’s Anna Maciag, Ph.D. show BBO-8520 blocks the “ON” and “OFF” states of KRASG12C, resulting in rapid KRAS inhibition.
  • First patient dosed June 2024.
Scientific structural figure
Controlling KRAS-PI3Kα Interaction Using Glue and Breaker Compounds. A “glue” molecule (blue) strengthens the interaction between KRAS (orange) and PI3Kα (cyan), promoting KRAS-driven PI3Kα activation. Through structure-guided design, the glue was transformed into a “breaker” molecule (red), which disrupts this interaction and blocks oncogenic KRAS-mediated PI3Kα activation.

BBO-10203

  • A first-in-class “breaker” compound that disrupts the cancer-driving signaling pathway caused by mutated RAS and PI3Kα proteins. Using a “molecular glue” compound, FNL’s Dhirendra Simanshu led the team in solving the first structure of the RAS-PI3Kα complex, which gave him the idea to use the breaker strategy to chemically disrupt this complex.
  • The clinical trial (NCT06625775) is enrolling adult patients with advanced solid tumors like metastatic breast cancer, lung cancer, and colorectal cancer.
  • First patient dosed in October 2024.

BBO-11818

  • A pan-KRAS inhibitor co-developed by the team led by Anna Maciag that acts against multiple KRAS mutants, including most common KRASG12D and KRASG12V mutants in both their “ON” and “OFF” states.
  • Patients with locally advanced solid tumors including non-small cell lung, pancreatic, colorectal cancers or other tumors with KRAS mutations are eligible to enroll in the trial.
  • The investigative treatment is being studied alone and in combination with targeted therapies and chemotherapy.
  • First patient dosed April 2025.

FNL scientists working on the National Cancer Institute’s RAS Initiative have partnered since 2017 with BBOT, and later with LLNL, under a Collaborative Research and Development Agreement (CRADA) to develop drugs targeting KRAS-driven cancers.