BBOT announced the publication of preclinical data in the peer-reviewed journal Science supporting BBO-10203's therapeutic potential across multiple tumor types. The study, titled "BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction," describes a first-in-class, orally available inhibitor that selectively disrupts the interaction between RAS proteins and PI3Kα without impairing insulin signaling.
Novel Mechanism of Action
BBO-10203 operates through a unique mechanism by covalently binding to a specific cysteine in the RAS-binding domain of PI3Kα. This binding effectively breaks the interaction between H-, N-, and KRAS proteins and PI3Kα, preventing oncogenic RAS-driven activation of the PI3Kα pathway. The compound demonstrated broad antitumor activity across tumor types with mutations in KRAS, PIK3CA, and HER2 amplification.
"Because the contribution of the second most mutated signaling pathway in human cancers remains underappreciated, we searched for an entirely novel molecular mechanism that is not encumbered by known metabolic liabilities to inhibit PI3Kα signaling," said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. "By blocking the crosstalk between RAS and PI3Kα in tumors, without interfering with physiological insulin signaling, we believe BBO-10203 represents a fundamentally differentiated approach with both biological and therapeutic promise."
Preclinical Efficacy and Safety Profile
In preclinical models, BBO-10203 treatment led to significant tumor growth inhibition across multiple tumor types without inducing hyperglycemia, a common side effect associated with traditional PI3K inhibitors. The compound demonstrated enhanced efficacy when combined with other anti-tumor agents, including CDK4/6 inhibitors, ER antagonists, HER2 inhibitors, and KRASG12C inhibitors.
Dhirendra Simanshu, PhD, lead author and Principal Scientist at Frederick National Laboratory for Cancer Research, explained the paradigm shift represented by this approach: "Rather than inhibiting RAS directly, it intercepts oncogenic signaling through effectors like PI3Kα, enabling tumor suppression while preserving essential physiological functions."
Clinical Development and Collaborative Research
BBO-10203 is currently being evaluated in the Phase 1 BREAKER-101 study (NCT06625775) in patients with locally advanced or metastatic HER2+ breast cancer, HR+/HER2- breast cancer, KRAS mutant advanced colorectal cancer, and KRAS mutant advanced non-small cell lung cancer.
The discovery of BBO-10203 resulted from a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. Frank McCormick, PhD, FRS, Chairman of the BBOT Board and Advisor to the National Cancer Institute's RAS Initiative, noted: "The role of the RAS:PI3Kα interaction in cancer biology has long been suspected but challenging to pin down precisely. Now we understand which cancers depend on this interaction, some quite unexpected. With BBO-10203 now in the clinic, there's real hope that these discoveries will translate into meaningful benefit for many cancer patients."
Company Background
BBOT is a clinical-stage biopharmaceutical company advancing novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), the company focuses on improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors.
