title: Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors.
abstract: 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.
authors.affiliation: Key Laboratory of Original New Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
authors.forename: Cunlong
authors.initials: C
authors.lastname: Zhang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhai
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Bizhu
authors.initials: B
authors.lastname: Chu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Ma
authors.forename: Yuzong
authors.initials: Y
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001185:Artificial Intelligence; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016315:Proto-Oncogene Proteins c-abl; D011759:Pyrrolidines; C032519:pyrrolidine