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

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

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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