On April 21, 2026 BridgeBio Oncology Therapeutics, Inc. ("BBOT") (Nasdaq: BBOT), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, reported new preclinical data in an oral presentation for BBO-10203, a first-in-class covalent small molecule RAS:PI3Kα breaker that selectively blocks the physical interaction between RAS and PI3Kα resulting in the inhibition of RAS-driven PI3Kα-AKT signaling in tumors with no observed hyperglycemia. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2026.
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"The interaction between RAS and PI3Kα plays a critical role in malignant cells," said Pedro J. Beltran, PhD, Chief Scientific Officer of BBOT. "BBO-10203 physically disrupts the interaction between RAS and PI3Kα, leading to signaling inhibition and tumor regressions. Importantly, unlike competing approaches, no hyperglycemia has been observed to date. In addition, BBO-10203’s ability to block RAS-mediated activation of PI3Kα is independent of the mutational status of either RAS or PI3Kα, which may enable treatment of a broader patient population. These data suggest that non-canonical RAS proteins play a key role in PI3Kα activation in HER2AMP cell lines. Furthermore, BBO-10203 demonstrates strong in vivo combination activity with HER2-targeted therapies, including tucatinib and trastuzumab, in HER2 AMP models."
Highlights from the oral presentation include:
BBO-10203 physically and allosterically disrupts the interaction between RAS and PI3Kα, leading to signaling inhibition without inhibiting the kinase activity of PI3Kα
BBO-10203 induces tumor regressions at 30 mg/kg QD and no hyperglycemia observed at 100 mg/kg QD
BBO-10203 shows that PI3Kα activity in HER2AMP cells is RAS-dependent
RAS RBD mutations recapitulate the pAKT and viability effects of breaker activity in HER2AMP cell lines
Non-canonical RAS signaling appears to be the dominant driver of pAKT in HER2AMP cell lines
BBO-10203 displays strong in vivo combination effects with HER2 inhibitors tucatinib or trastuzumab in HER2AMP models
The oral presentation is titled "The RAS:PI3Kα breaker BBO-10203 inhibits PI3Kα/AKT activity in HER2AMP models through non-canonical RAS signaling blockade." A copy of the presentation will be available on the "Publications" page of the BBOT website following the conference.
About BBO-10203
BBO-10203 is an orally bioavailable small molecule with a novel mechanism of action designed to inhibit the physical interaction between RAS and PI3Kα, inhibiting RAS-driven PI3Kα-AKT signaling in tumors. BBO-10203 binds directly and covalently to the RAS-binding domain of PI3Kα, preventing its activation by KRAS, HRAS and NRAS, reducing downstream signaling and tumor growth. It is a protein-protein inhibitor and not a kinase inhibitor, enabling inhibition of RAS-driven PI3Kα-AKT signaling in tumors without the risk of hyperglycemia. Importantly, BBO-10203’s ability to block RAS activation of PI3Kα is agnostic to the mutational status of either RAS or PI3Kα. In addition to a potentially differentiated safety profile, BBO-10203 could be combined with direct KRAS inhibitors, such as BBO-8520 and BBO-11818, or drugs that target HER2 or ER receptors. BBO-10203 is being evaluated in the Phase 1 BREAKER-101 trial (NCT06625775) for patients with locally advanced or metastatic HER2+ breast cancer, HR+/HER2- breast cancer, KRAS-mutant colorectal cancer, and KRAS-mutant non-small cell lung cancer. Updated Phase 1 clinical data are expected in the second half of 2026.
(Press release, BridgeBio Oncology Therapeutics, APR 21, 2026, View Source [SID1234664654])