BBOT Presents First-in-Class RAS:PI3Kα Breaker BBO-10203 Data at SABCS, Launches Phase 1 Trial
核心洞察
BridgeBio Oncology Therapeutics (搜索) presented late-breaking preclinical data on BBO-10203, a first-in-class covalent small molecule that blocks RAS (搜索)-PI3Kα (搜索) protein interactions at the San Antonio Breast Cancer (搜索) Symposium.
The compound demonstrated robust anti-tumor activity in breast cancer (搜索) models without inducing hyperglycemia, addressing a key limitation of current PI3K inhibitors.
BBOT (搜索) has initiated the Phase 1 BREAKER-101 trial evaluating BBO-10203 in multiple cancer types, with initial clinical data expected in the first half of 2026.
BridgeBio Oncology Therapeutics (搜索) (BBOT (搜索)) announced compelling preclinical data for BBO-10203, a novel therapeutic designed to disrupt the physical interaction between RAS (搜索) and PI3Kα (搜索) proteins, at the San Antonio Breast Cancer (搜索) Symposium (SABCS). The company simultaneously presented details of its Phase 1 BREAKER-101 clinical trial, marking a significant milestone in targeting RAS-pathway malignancies with a differentiated mechanism of action.
Novel Mechanism Addresses PI3K Inhibitor Limitations
BBO-10203 represents a paradigm shift from traditional PI3K inhibitors by functioning as a protein-protein interaction breaker rather than a kinase inhibitor. The compound covalently binds to cysteine 242 in the RAS (搜索)-binding domain of PI3Kα (搜索), preventing activation by KRAS (搜索), HRAS, and NRAS while maintaining pathway inhibition without hyperglycemia risk.
"Although PI3Kα (搜索) inhibitors have provided an important treatment option for HR+/HER2 (搜索)- and HER2+ breast cancer (搜索) with PI3Kα mutations, their use is often limited by dose-dependent hyperglycemia and reduced treatment duration," said Pedro Beltran, PhD, Chief Scientific Officer of BBOT (搜索). "Our preclinical work shows that BBO-10203 offers a differentiated mechanism by disrupting the RAS (搜索)–PI3Kα interaction rather than inhibiting PI3Kα's kinase activity."
Robust Preclinical Efficacy Data
The late-breaking preclinical findings demonstrated several key advantages of BBO-10203's approach. Oral administration resulted in robust pharmacokinetics with dose- and time-dependent inhibition of pAKT (搜索) signaling. Critically, the compound did not induce hyperglycemia or hyperinsulinemia in oral glucose tolerance tests, addressing a major tolerability concern with current PI3K inhibitors.
BBO-10203 showed significant activity both as monotherapy and in combination with standard-of-care therapies including fulvestrant and ribociclib in ER+ HER2 (搜索)- breast cancer (搜索) models harboring either PIK3CA helical or kinase domain mutations. The compound demonstrated similar efficacy to STX-478 (LY4064809), a PIK3CA mutant-selective inhibitor, in models with PIK3CA kinase domain mutations.
Notably, BBO-10203 also exhibited activity in combination with ribociclib in ER+ HER2 (搜索)- breast cancer (搜索) models with wild-type PIK3CA, highlighting its potential utility across diverse genetic backgrounds.
Clinical Translation Through BREAKER-101 Trial
BBOT (搜索) has initiated BREAKER-101 (NCT06625775), a first-in-human, multicenter, open-label Phase 1a/1b study evaluating BBO-10203's safety, tolerability, pharmacokinetics, and preliminary antitumor activity. The trial encompasses both monotherapy and combination approaches with trastuzumab, fulvestrant ± ribociclib, or FOLFOX + bevacizumab.
The study targets patients with locally advanced or metastatic HER2 (搜索)+ breast cancer (搜索), HR+/HER2- breast cancer, KRAS (搜索) mutant colorectal cancer (搜索), and KRAS mutant non-small cell lung cancer (搜索). The design includes dose escalation and expansion phases, with key endpoints focusing on safety, tolerability, anti-tumor activity, and pharmacokinetics. Intracranial activity will be evaluated as an exploratory endpoint.
"PIK3CA mutations are common, particularly in HR+/HER2 (搜索)- and HER2+ advanced breast cancer (搜索)," noted Andreas Varkaris, MD, PhD, Attending Physician and Investigator at Massachusetts General Hospital and a BREAKER-101 investigator. "We now look forward to a new generation of inhibitors, such as BBO-10203, that can more selectively target the mutant enzyme without affecting normal cells, potentially enabling us to treat more patients."
Broad Therapeutic Potential
BBO-10203's mechanism offers unique advantages beyond improved tolerability. The compound's ability to block RAS (搜索) activation of PI3Kα (搜索) is agnostic to the mutational status of either RAS or PI3Kα, potentially expanding its therapeutic utility. Additionally, the differentiated safety profile may enable combinations with direct KRAS (搜索) inhibitors such as BBO-8520 and BBO-11818, or drugs targeting HER2 (搜索) or ER receptors.
The study is currently enrolling patients in the United States and Australia, with initial Phase 1 clinical data expected in the first half of 2026. This timeline positions BBO-10203 as a potential next-generation therapy for RAS (搜索)-pathway driven malignancies, addressing critical unmet needs in oncology through its innovative protein-protein interaction disruption approach.