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BridgeBio Oncology Therapeutics (Nasdaq: BBOT) has announced promising preclinical data for its novel compound, BBO-10203, indicating a selective disruption of the RAS:PI3Kα interaction. This interaction is crucial in driving tumor growth, particularly in cancers harboring KRAS mutations. The data reveals that BBO-10203 covalently binds to PI3Kα at cysteine 242, effectively inhibiting RAS-driven PI3Kα-AKT signaling without the adverse effects of hyperglycemia or hyperinsulinemia, common drawbacks of existing PI3Kα inhibitors.
In vivo studies showcase compelling results, including oral bioavailability, complete target engagement at low nanomolar concentrations, and significant monotherapy anti-tumor activity across various KRAS-mutant models (CDX, PDX, and GEM). Notably, when combined with BridgeBio’s KRAS inhibitors, BBO-8520 and BBO-11818, the drug demonstrated deep tumor regressions at well-tolerated doses. These findings are particularly encouraging as they suggest a potential synergistic effect, tackling both the RAS and PI3Kα pathways simultaneously.
Currently, BBO-10203 is undergoing evaluation in the Phase 1 BREAKER-101 trial. Initial Phase 1 clinical data is anticipated in the first half of 2026. Investors and the medical community are eagerly awaiting these results which will provide a crucial insight into the drug’s safety and efficacy in human trials.
BridgeBio Oncology Therapeutics (Nasdaq: BBOT) ha riportato dati preclinici che mostrano BBO-10203 che selettivamente interrompe l’interazione RAS:PI3Kα, legando covalentemente PI3Kα a Cisteina 242 e inibendo la segnalazione RAS-driven PI3Kα-AKT senza indurre iperglicemia o iperinsulinemia nei test di tolleranza al glucosio.
Studi in vivo hanno mostrato biodisponibilità orale, completo engagement del bersaglio a livelli nanomolari bassi, robusta attività anti-tumorale in monoterapia su modelli KRAS-mutant CDX, PDX e GEM, e profonde regressioni tumorali quando combinato con gli inibitori KRAS di BBOT BBO-8520 e BBO-11818 a dosi ben tollerate. Breaker-101 di Fase 1 è in arruolamento; i primi dati clinici di Fase 1 sono attesi nel H1 2026.
BridgeBio Oncology Therapeutics (Nasdaq: BBOT) informó datos preclínicos que muestran BBO-10203 rompe selectivamente la interacción RAS:PI3Kα, uniendo covalentemente PI3Kα en la cisteína 242 e inhibiendo la señalización PI3Kα-AKT impulsada por RAS sin inducir hiperglucemia o hiperinsulinemia en las pruebas de tolerancia a la glucosa.
Los estudios in vivo mostraron biodisponibilidad oral, compromiso completo del objetivo a niveles bajos de nanomoles, actividad antitumoral monoterapéutica robusta en modelos KRAS-mutant CDX, PDX y GEM, y profundas regresiones tumorales cuando se combina con los inhibidores KRAS de BBOT BBO-8520 y BBO-11818 en dosis bien toleradas. Breaker-101 de Fase 1 se está inscribiendo; se esperan los primeros datos clínicos de Fase 1 en H1 2026.
BridgeBio Oncology Therapeutics (나스닥: BBOT)는 BBO-10203가 선택적으로 RAS:PI3Kα 상호작용을 끊고, 시스테인 242에서 PI3Kα에 공유 결합하며, RAS-주도 PI3Kα-AKT 신호 전달을 억제하고 포도당 내성 검사에서 고혈당증이나 고인슐린혈증을 유발하지 않는다는 전임상 데이터를 보고했다.
생체 내 연구에서 경구 생체이용성, 낮은 나노몰 수준에서의 표적 완전 Engagement, KRAS 변이된 CDX, PDX 및 GEM 모델에서의 단일요법 항종양 활성, 그리고 BBOT의 KRAS 억제제인 BBO-8520과 BBO-11818과의 병용 시 잘 견디는 용량에서의 깊은 종양 억제 효과가 나타났다. 1상 BREAKER-101은 등록 중이며, 2026년 상반기에 초기 1상 임상 데이터가 기대된다.
BridgeBio Oncology Therapeutics (Nasaq: BBOT) a présenté des données précliniques montrant que BBO-10203 rompt sélectivement l’interaction RAS:PI3Kα, se liant de manière covalente à PI3Kα à la cystéine 242 et inhibant la signalisation PI3Kα-AKT dirigée par RAS sans induire d’hyperglycémie ou d’hyperinsulinémie lors des tests de tolérance au glucose.
Les études in vivo ont montré une biodisponibilité orale, un engagement complet de la cible à de faibles niveaux nanomolaires, une activité anti-tumorale robuste en monothérapie sur des modèles KRAS-mutant CDX, PDX et GEM, et des régressions tumorales profondes lorsque associées aux inhibiteurs KRAS de BBOT BBO-8520 et BBO-11818 à des doses bien tolérées. Phase 1 BREAKER-101 est en cours d’inscription; les premiers résultats cliniques de la Phase 1 sont attendus au 1er semestre 2026.
BridgeBio Oncology Therapeutics (Nasdaq: BBOT) meldete präklinische Daten, die zeigen, dass BBO-10203 selektiv die RAS:PI3Kα-Interaktion bricht, covalente Bindung an PI3Kα an Cystein 242 eingeht und die RAS-getriebene PI3Kα-AKT-Signalgebung hemmt, ohne Hyperglykämie oder Hyperinsulinämie in Glukosetoleranztests zu verursachen.
In Vivo-Studien zeigten orale Bioverfügbarkeit, vollständiges Target-Engagement bei niedrigen Nanomolar-Werten, robuste Monotherapie-Antitumoraktivität über KRAS-mutante CDX-, PDX- und GEM-Modelle und tiefe Tumorregressionen, wenn mit BBOTs KRAS-Inhibitoren BBO-8520 und BBO-11818 bei gut verträglichen Dosen kombiniert. Phase 1 BREAKER-101 wird rekrutiert; erste klinische Daten der Phase 1 werden in H1 2026 erwartet.
BridgeBio Oncology Therapeutics (بورصة ناسداك: BBOT) أظهرت بيانات ما قبل السريرية أن BBO-10203 يكسر تفاعل RAS:PI3Kα بشكل انتقائي، ويرتبط بشكل تساهمي بـ PI3Kα عند الك cysteine 242 ويقلل الإشارة PI3Kα-AKT المدفوعة بـ RAS دون أن يسبب فرط سكر الدم أو فرط الأنسولين في اختبارات تحمل الجلوكوز.
أظهرت الدراسات الحياتية توفر حيوي فَموي كامل الالتزام بالهدف عند مستويات نانومول منخفضة، ونشاط مضاد للأورام قوي كعلاج أحادي عبر نماذج KRAS-mutant CDX وPDX وGEM، وتراجعات ورمية عميقة عند دمجه مع مثبطات KRAS BBOT BBO-8520 و BBO-11818 عند جرعات جيدة التحمل. BREAK-101 للمرحلة 1 جارٍ التوظيف؛ من المتوقع ظهور بيانات سريرية أولية للمرحلة 1 في النصف الأول من 2026.
BridgeBio Oncology Therapeutics (纳斯达克：BBOT) 报告了前临床数据，显示 BBO-10203 能选择性地打断 RAS:PI3Kα 的相互作用，在 C242 位点共价结合 PI3Kα，并抑制由 RAS 驱动的 PI3Kα-AKT 信号通路，同时在葡萄糖耐量测试中不诱发高血糖或 高胰岛素血症。
体内研究显示口服生物利用度、在低纳摩尔水平下的完全靶点参与、在 KRAS 突变的 CDX、PDX 和 GEM 模型中的单药抗肿瘤活性，以及与 BBOT 的 KRAS 抑制剂 BBO-8520 和 BBO-11818 以良好耐受剂量联合时的深部肿瘤缩小。阶段 1 BREAKER-101 正在招募；预计在 2026 年上半年获得初步阶段 1 临床数据。
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
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.
10/25/2025 – 12:30 PM
Key highlights from BridgeBio Oncology Therapeutics’ press release:
- 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 KRASG12C 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) — The oncology landscape is witnessing a potential breakthrough as BridgeBio Oncology Therapeutics, Inc. (Nasdaq: BBOT) unveils new preclinical findings on its investigational drug, BBO-10203. This clinical-stage biopharmaceutical company, focusing on malignancies driven by the RAS pathway, is generating buzz with its innovative approach to tackling tumor growth. The focal point of the excitement is the compound’s ability to selectively block the physical interaction between RAS and PI3Kα, thereby inhibiting RAS-driven PI3Kα-AKT signaling in tumors without the risk of the hyperglycemia typically associated with PI3Kα inhibitors. This selective action could position BBO-10203 as a significant improvement over existing treatment options, offering a potentially safer and more effective therapeutic profile. Furthermore, observed synergistic effects in combination with the company’s own KRAS inhibitors, BBO-8520 and BBO-11818, adds another layer of intrigue for potential investors. These data, presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, are being closely scrutinized by analysts and clinicians alike.
FAQ
What is BBO-10203 and how does it work for KRAS-mutant tumors (BridgeBio)?
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 (BridgeBio)?
No; preclinical oral glucose tolerance tests showed BBO-10203 did not induce hyperglycemia or hyperinsulinemia.
What combination activity was observed with BBO-10203 and BridgeBio 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 (BridgeBio)?
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 BridgeBio’s KRAS inhibitors in humans (BridgeBio)?
Yes; the company plans combination evaluations in BREAKER-101, including studies with its KRAS inhibitors.
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