BBO-10203 (Compound 758) is an orally active PI3Kα-Ras interaction disruptor that binds to the RAS-binding domain (RBD) of PI3Kα, disrupting the Ras-PI3Kα interaction and inhibiting Akt activation. It does not significantly affect PI3Kα kinase activity to avoid hyperglycaemia and hyperinsulinaemia, and exhibits activity against KRAS-mutant tumours.

BBO-10203 blocks the interaction between KRAS-G12D and PI3Kα in HEK293T cells with an IC50 of 6 nM, without affecting the binding between KRAS-G12D and protein kinase CRAF or inhibiting the in vitro kinase activity of PI3Kα. BBO-10203 exhibits an IC50 < 10 nM against most HER2 gene-amplified cell lines and is sensitive to PIK3CA spiral mutations in cell lines. [1][2]

In fasting male mice undergoing an oral glucose tolerance test, 300 mg/kg BBO-10203 did not affect glucose metabolism, while 50 mg/kg aprelis was associated with hyperglycaemia and hyperinsulinaemia.
In xenograft mouse models with KRAS G12X mutations, with or without PIK3CA mutations, BBO-10203 (10–100 mg/kg, oral, once daily, for 28 days) exhibited dose-dependent tumour volume reduction effects and antitumour efficacy in several subcutaneous xenograft models with multiple KRAS mutations. [1]