Discovery of2-(4-Ureido-piperidin-1-yl)-4-morpholinothieno[3,2-D] Pyrimidines as Orally Bioavailable Phosphoinositide-3-KinaseInhibitors with In Vitro and In Vivo Antitumor Efficacy in Triple-Negative Breast Cancer

Abstract The phosphoinositide-3-kinase-α is a key regulator of tumor progression across different cancers, including triple-negative breast cancer. Herein, we explored thienopyrimidine and pyridofuropyrimidine cores to identify a PI3K-α inhibitor for the treatment of TNBC with favorable ADME properties. Structure-guided drug design and lead optimization efforts led to the identification of piperidine urea analog 50b as a PI3K-α inhibitor, which effectively inhibits the growth of MDA-MB-231 cells by targeting p110α, MAP kinase pathways, enhancing the expression of apoptotic proteins and impeding the cell’s migratory capabilities. Compound 50b occupies the PI3K-α hinge pocket and forms H-bonding with VAL851, as well as with GLN859, a nonconserved residue linked to isoform selectivity. It exhibited a favorable ADME/PK profile, with 56% oral bioavailability, and demonstrated efficacy in the MDA-MB-231 xenograft model at peroral doses ranging from 25 to 75 mg/kg. Acute and repeated-dose toxicity studies confirmed an excellent safety profile, suggesting its potential for further development as a lead molecule for TNBC.