Preclinical Data Presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Support Potential of BBO-10203, a First-in-Class RAS:PI3Kα Breaker That Inhibits KRAS-Mutant Tumor Growth without Inducing Hyperglycemia

Rhea-AI Summary

BridgeBio Oncology Therapeutics (Nasdaq: BBOT) reported preclinical data showing BBO-10203 selectively breaks the RAS:PI3Kα interaction, covalently binding PI3Kα at cysteine 242 and inhibiting RAS-driven PI3Kα-AKT signaling without inducing hyperglycemia or hyperinsulinemia in glucose tolerance testing.

In vivo studies showed oral bioavailability, complete target engagement at low nanomolar levels, robust monotherapy anti-tumor activity across KRAS-mutant CDX, PDX and GEM models, and deep tumor regressions when combined with BBOT’s KRAS inhibitors BBO-8520 and BBO-11818 at well-tolerated doses. Phase 1 BREAKER-101 is enrolling; initial Phase 1 clinical data expected in H1 2026.

Positive

• Covalent PI3Kα binding at Cys242
• Complete target engagement at low nanomolar concentrations
• Oral bioavailability with dose- and time-dependent pAKT inhibition
• No hyperglycemia or hyperinsulinemia in oral glucose tolerance tests
• Deep tumor regressions in multiple KRAS-mutant in vivo models

Negative

• Evidence is preclinical; no clinical efficacy data reported yet
• Therapeutic benefit in patients pending initial Phase 1 readouts expected H1 2026

Insights

Translational oncology expert

Preclinical data show BBO-10203 breaks RAS:PI3Kα, inhibits pAKT, and avoids hyperglycemia; clinical Phase 1 data are expected in first half of 2026.

BBO-10203 binds covalently to PI3Kα at cysteine 242 in the RAS binding domain and blocks the RAS‑PI3Kα physical interaction. This mechanism produces complete cellular target engagement at low nanomolar concentrations, oral bioavailability, and dose‑ and time‑dependent inhibition of pAKT across KRAS‑mutant cancer cell lines.

The compound showed robust monotherapy anti‑tumor activity and well‑tolerated combination activity with BBOT’s KRAS inhibitors BBO-8520 and BBO-11818 in CDX, PDX, and GEM models, with no induction of hyperglycemia or hyperinsulinemia during an oral glucose tolerance test. These facts suggest a differentiated safety signal for PI3Kα pathway targeting versus historical PI3Kα inhibitors that cause dose‑limiting hyperglycemia.

Key dependencies and near‑term milestones are clear: ongoing enrollment in the Phase 1 BREAKER-101 trial and initial Phase 1 clinical data expected in first half of 2026. Watch for safety data on glucose metabolism, pharmacokinetic target coverage, and objective anti‑tumor responses in those data sets over the next 6–12 months.

• Data demonstrate BBO-10203 blocks RAS-mediated activation of PI3Kα and strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism
• Robust monotherapy activity, as well as combination activity with BBOT’s KRAS^G12C ON/OFF inhibitor, BBO-8520, and panKRAS inhibitor, BBO-11818, was observed at well-tolerated dose levels in a panel of KRAS-mutant models
• The combination of a KRAS inhibitor with a PI3Kα pathway inhibitor may maximize the response rate and reduce the development of adaptive resistance mechanisms due to full inhibition of both MAPK and PI3Kα signaling
• BBOT-10203 is currently being evaluated in the Phase 1 BREAKER-101 trial for patients with HER2+ amplified or HR+/HER2- breast cancer, and KRAS mutant colorectal or non-small cell lung cancer with initial Phase 1 clinical data expected in the first half of 2026

SOUTH SAN FRANCISCO, Calif., Oct. 25, 2025 (GLOBE NEWSWIRE) -- BridgeBio Oncology Therapeutics, Inc. (“BBOT”) (Nasdaq: BBOT), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced new preclinical data showing BBO-10203 selectively and specifically blocks the physical interaction between RAS and PI3Kα, resulting in the inhibition of RAS-driven PI3Kα-AKT signaling in tumors without the risk of hyperglycemia. In addition, combination activity with BBOT’s KRAS^G12C ON/OFF inhibitor, BBO-8520, and panKRAS inhibitor, BBO-11818, was observed at well tolerated dose levels in a panel of KRAS mutant models. The data were presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

“Aberrant activation of the PI3Kα pathway is among the most common oncogenic drivers across human cancers and leads to promotion of tumor growth, survival, and resistance to standard therapies,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “Current PI3Kα inhibitors are hindered by dose-limiting toxicities like hyperglycemia, which restrict target coverage, limit the number of eligible patients, and shorten the duration of treatment – leaving a significant unmet medical need. We’ve designed BBO-10203 to break the interaction between RAS and PI3Kα and inhibit RAS-mediated activation of the PI3Kα pathway. These preclinical data demonstrate BBO-10203 can accomplish this in in vivo studies without affecting glucose metabolism and achieve robust anti-tumor activity both as a monotherapy and in combination with our KRAS inhibitors, BBO-8520 and BBO-11818.”

These preclinical findings demonstrate BBO-10203 covalently binds PI3Kα on cysteine 242 in the RAS binding domain, breaking the protein-protein interaction between RAS and PI3Kα. Monotherapy results show achievement of complete cellular target engagement at low nanomolar concentrations and oral bioavailability with robust dose- and time-dependent inhibition of pAKT across diverse human cancer cell lines with KRAS mutations. Importantly, BBO-10203 does not induce hyperglycemia or hyperinsulinemia during an oral glucose tolerance test. In a panel of cell-line derived xenograft (CDX), patient-derived xenograft (PDX), and genetically engineered mouse (GEM) models, treatment with BBO-10203, both as a monotherapy and in combination with BBO-8520, BBOT’s direct inhibitor of KRAS^G12C in both the ON and OFF states, and with BBO-11818, the company’s panKRAS inhibitor targeting mutant KRAS in both the ON and OFF states with strong potency against KRAS^G12D and KRAS^G12V mutants, show robust anti-tumor activity. Importantly, the combination of BBO-10203 + BBO-8520 and BBO-10203 + BBO-11818 induces deep tumor regressions through direct effects on tumor cell proliferation and apoptosis and are well-tolerated.

BBO-10203 is currently being evaluated in the Phase 1 BREAKER-101 trial for patients with HER2+ amplified or HR+/HER2- breast cancer, and KRAS mutant colorectal or non-small cell lung cancer as a monotherapy and in combination with standard of care treatment, and will be evaluated in combination with KRAS inhibitors.

“We are pleased to share these preclinical data on BBO-10203’s potential as a RAS:PI3Kα breaker,” said Eli Wallace, PhD, Chief Executive Officer of BBOT. “By breaking the interaction between RAS and PI3Kα while preserving normal insulin signaling, these results further support our belief that BBO-10203 represents a truly differentiated approach with significant biological and therapeutic potential. We continue to enroll patients in our Phase 1 BREAKER-101 trial and look forward to expanding into combination studies, including with our own 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 available on the “Publications” page of the BBOT website following the conference.

About BBO-10203
BBO-10203 is a first-in-class small molecule which breaks the protein-protein interaction between RAS and PI3Kα and inhibits RAS-mediated activation of the PI3Kα pathway. It selectively disrupts oncogenic RAS-PI3Kα signaling while sparing insulin-mediated glucose uptake, potentially maintaining efficacy with reduced risk of hyperglycemia or hyperinsulinemia. BBO-10203 is currently being evaluated in the Phase 1 BREAKER-101 trial 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. Initial Phase 1 clinical data are expected in the first half of 2026.

About BBOT
BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, please visit www.bbotx.com and follow us on LinkedIn.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended, and other federal securities laws. Any statements in this press release that are not historical facts may be deemed forward-looking statements,  which generally are accompanied by words such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “should,” “would,” “plan,” “predict,” “potential,” “seem,” “seek,” “future,” “outlook” and similar expressions that predict or indicate future events or trends. These statements are based on various assumptions, whether or not identified in this press release, and are the current expectations of BBOT’s management and are not predictions of actual performance. Many actual events and circumstances are beyond the control of BBOT. These forward-looking statements are subject to a number of risks and uncertainties, including changes in domestic and foreign business, market, financial, political, and legal conditions; risks relating to the uncertainty of the projected financial information with respect to BBOT; risks related to the approval of BBOT’s product candidates and the timing of expected regulatory and business milestones, including the progress of enrollment in clinical trials and availability of data from ongoing and planned clinical trials; the impact of competitive products; risks relating to BBOT’s ability to obtain sufficient supply of materials; and those factors discussed in documents BBOT has filed or will file with the U.S. Securities and Exchange Commission.

In addition, forward-looking statements reflect BBOT’s expectations, plans, or forecasts of future events and views as of the date of this press release and are qualified in their entirety by reference to the cautionary statements herein. BBOT anticipates that subsequent events and developments will cause BBOT’s assessments to change. These forward-looking statements should not be relied upon as any guarantee, assurance, prediction or definitive statement of fact or probability or as representing BBOT’s assessments as of any date subsequent to the date of this press release. Neither BBOT, nor any of its affiliates undertake any obligation to update these forward-looking statements, except as required by law.

BBOT Contacts:

Investor Contact:
Heather Armstrong, Head of Investor Relations
BBOT
Investors@BBOTx.com

Media Contact:
Jake Robison
Inizio Evoke Comms
Jake.robison@inizioevoke.com

FAQ

What is BBO-10203 and how does it work for KRAS-mutant tumors (BBOT)?

BBO-10203 is a first-in-class RAS:PI3Kα breaker that covalently binds PI3Kα at Cys242, blocking RAS-mediated PI3Kα-AKT signaling in KRAS-mutant models.

Does BBO-10203 cause hyperglycemia in preclinical testing (BBOT)?

No; preclinical oral glucose tolerance tests showed BBO-10203 did not induce hyperglycemia or hyperinsulinemia.

What combination activity was observed with BBO-10203 and BBOT KRAS inhibitors?

Combining BBO-10203 with BBO-8520 or BBO-11818 produced deep tumor regressions at well-tolerated dose levels in multiple KRAS-mutant models.

What is the clinical status of BBO-10203 (BBOT)?

BBO-10203 is in the Phase 1 BREAKER-101 trial for select breast, colorectal, and NSCLC indications; initial Phase 1 data are expected in H1 2026.

Will BBO-10203 be tested with BBOT’s KRAS inhibitors in humans (BBOT)?

Yes; the company plans combination evaluations in BREAKER-101, including studies with its KRAS inhibitors.