ArticleCancer discovery2025
Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Molecular Mechanisms and Therapeutic Advances in KRAS G12C-Mutant Non-Small Cell Lung Cancer: Toward Mechanism-Guided Longitudinal Management.Cancer innovation · 2026Review
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- RAS signaling at the crossroads of radioresistance and tumor immunity.Journal for immunotherapy of cancer · 2026Review
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- Single-Sequence Deep Learning Delivers Crystal-Quality Models of Covalent K-Ras G12 Hotspot Complexes.IUBMB life · 2026Article
- Current advances in immunotherapy for KRAS-Mutant pancreatic cancer.Clinical and experimental medicine · 2026Review
- Combining cutting edge computational and experimental methods for targeting KRAS mutations in non-small cell lung cancer.Expert opinion on drug discovery · 2026Review
- Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASbioRxiv : the preprint server for biology · 2026Article
- AURKA/PHB2 signaling drives acquired resistance to KRASCell death discovery · 2026Article
- Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants.Cancer discovery · 2026Article
- Disulfide tethering reveals cryptic pockets in oncogenic KRAS.Communications chemistry · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases.The Journal of biological chemistry · 2026Article
- Pan-KRAS inhibition: unlocking broad-spectrum targeted therapy forCancer biology & medicine · 2026Article
- Covalent modification of a glutamic acid inspired by HaloTag technology.Nature communications · 2026Article
- Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.Journal of medicinal chemistry · 2026Article
- KRAS Inhibition in Pancreatic Ductal Adenocarcinoma.Journal of clinical medicine · 2026Review
- Therapeutic inhibition of RAS in non-small cell lung cancer.Frontiers in oncology · 2026Review
- Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles.Journal of the American Chemical Society · 2025Article
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Authors and funding
35 authors.
Funding
Abstract
Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.
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