Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants

  • Cancer Discov. 2026 Mar 6:OF1-OF20. doi: 10.1158/2159-8290.CD-25-1280.
Carlos Stahlhut  1 ,  Anna E Maciag  2 ,  Kyle A Sullivan  #  1 ,  Kanchan Singh  #  1 ,  Nadege Gitego  #  1 ,  Zuhui Zhang  1 ,  Albert H Chan  2 ,  Alok K Sharma  2 ,  Patrick A Alexander  2 ,  Jin Shu  1 ,  Yue Yang  1 ,  Megan Rigby  2 ,  Roger Ma  2 ,  Saman Setoodeh  1 ,  Brian P Smith  2 ,  Jun Pei  3 ,  Dana Rabara  2 ,  Erik K Larsen  2 ,  David M Turner  2 ,  Cathy Zhang  1 ,  Cindy Feng  1 ,  Siyu Feng  1 ,  James P Stice  1 ,  Rui Xu  1 ,  Ken Lin  1 ,  Andrew G Stephen  2 ,  Felice C Lightstone  3 ,  Chunmei Ji  1 ,  Keshi Wang  1 ,  Dhirendra K Simanshu  2 ,  Dwight V Nissley  2 ,  Eli Wallace  1 ,  Bin Wang  1 ,  Kerstin W Sinkevicius  1 ,  Frank McCormick  2  4 ,  Pedro J Beltran  1
Affiliations
  • 1. BridgeBio Oncology Therapeutics, South San Francisco, California.
  • 2. NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
  • 3. Physical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California.
  • 4. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
  • # Contributed equally.
PMID: 41790032 DOI: 10.1158/2159-8290.CD-25-1280
Abstract

Although KRASG12C-specific inhibitors have been introduced, no approved targeted therapies exist for Other clinically significant KRAS mutants, including KRASG12D and KRASG12V. We discovered BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds in the Switch-II/Helix 3 pocket, inducing conformational changes incompatible with effector binding, and demonstrates high-affinity binding to mutant KRAS with strong selectivity over NRAS and HRAS. BBO-11818 potently inhibited MAPK signaling and cellular viability specifically in KRAS-driven lines and produced tumor regressions in KRAS-mutant xenograft models. Combination studies with anti-PD-1, anti-EGFR antibodies, and a RAS:PI3Kα breaker compound showed enhanced efficacy. BBO-11818 has entered phase I clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079).

Significance: We discovered BBO-11818, a potent and selective noncovalent KRAS inhibitor with activity against multiple KRAS mutants in both the active (ON) and inactive (OFF) states. BBO-11818 addresses the need for KRAS inhibitors targeting clinically relevant mutants such as KRASG12D and KRASG12V, either as monotherapy or in combination.

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