BridgeBio Oncology Therapeutics, Inc. (“BBOT”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, has presented new preclinical data at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The data suggest that BBO-10203, a novel RAS:PI3Kα breaker, effectively inhibits tumor growth associated with KRAS mutations without inducing hyperglycemia.
The findings indicate that BBO-10203 selectively disrupts the interaction between RAS and PI3Kα, leading to a significant reduction in RAS-driven PI3Kα-AKT signaling in tumor cells. Notably, this compound did not affect glucose metabolism, addressing a critical limitation of existing PI3Kα inhibitors that often cause dose-limiting toxicities such as hyperglycemia.
“Aberrant activation of the PI3Kα pathway is one of the most prevalent oncogenic drivers in human cancers, leading to enhanced tumor growth and survival,” stated Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “Current PI3Kα inhibitors face challenges due to toxicities that restrict their use. We designed BBO-10203 to inhibit the interaction between RAS and PI3Kα, achieving significant anti-tumor activity without compromising glucose metabolism.”
In preclinical studies, BBO-10203 demonstrated complete cellular target engagement at low nanomolar concentrations, showing robust inhibition of pAKT across various human cancer cell lines harboring KRAS mutations. Importantly, the compound did not induce hyperglycemia or hyperinsulinemia during oral glucose tolerance tests.
Furthermore, the data revealed that BBO-10203, when administered alone or in combination with BBOT”s KRASG12C ON/OFF inhibitor, BBO-8520, and the panKRAS inhibitor BBO-11818, exhibited strong anti-tumor activity in multiple KRAS mutant models. The combinations resulted in significant tumor regressions through effects on tumor cell proliferation and apoptosis, all while being well-tolerated by the subjects.
BBO-10203 is currently under evaluation in the Phase 1 BREAKER-101 trial for patients with HER2+ amplified or HR+/HER2- breast cancer, as well as KRAS mutant colorectal and non-small cell lung cancers. The initial Phase 1 clinical data is anticipated in the first half of 2026.
“We are excited to share these findings regarding the potential of BBO-10203 as a RAS:PI3Kα breaker,” remarked Eli Wallace, PhD, CEO of BBOT. “Our approach not only disrupts the harmful RAS-PI3Kα interaction but also preserves normal insulin signaling, reinforcing our belief in the therapeutic promise of BBO-10203. We are continuing to enroll participants in the BREAKER-101 trial and look forward to exploring combination therapies, including those with our KRAS inhibitors.”
A copy of the poster titled “BBO-10203, a first-in-class, orally bioavailable, selective breaker of the RAS:PI3Kα interaction inhibits tumor growth alone and in combination with KRAS inhibitors in KRAS mutant models without inducing hyperglycemia” will be accessible on the “Publications” page of the BBOT website following the conference.
BBO-10203 is a pioneering small molecule designed to break the protein-protein interaction between RAS and PI3Kα, inhibiting RAS-mediated activation of the PI3Kα pathway while sparing insulin-mediated glucose uptake. This unique mechanism may allow for effective treatment with a reduced risk of hyperglycemia or hyperinsulinemia. It is currently being assessed in the Phase 1 BREAKER-101 trial targeting several cancer types.
BBOT is dedicated to advancing a next-generation pipeline of innovative small molecule therapeutics aimed at addressing RAS and PI3Kα driven malignancies to improve patient outcomes.
This press release contains forward-looking statements based on current expectations and assumptions regarding BBOT”s future performance and is qualified by cautionary statements herein. BBOT is not obligated to update any forward-looking statements except as required by law.
BBOT Contacts: Investor Contact: Heather Armstrong, Head of Investor Relations, BBOT, ; Media Contact: Jake Robison, Inizio Evoke Comms,
