Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors

Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition. Three compounds 5k– m (IC 50 = 3∼4 μM) showed the promising cytoxicity against K562 cell line and moderate inhibition against Abl and PI3K kinases. [Display omitted] ► Novel Abl and PI3K dual inhibitors bearing (S)-3-aminopyrrolidine was identified by SVM. ► Most compounds demonstrated promising cytoxicity against K562 cell line. ► The promising cell activity might be due to the synergic effect of inhibiting both Abl and PI3K.