title: A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling.
abstract: The rational design of selective kinase inhibitors remains a great challenge. Here we describe a physics-based approach to computationally modeling the kinase inhibitor selectivity profile. We retrospectively assessed this protocol by computing the binding profiles of 17 well-known kinase inhibitors against 143 kinases. Next, we predicted the binding profile of the chemotherapy drug mitoxantrone, and chose the predicted top five kinase targets for in vitro kinase assays. Remarkably, mitoxantrone was shown to possess low nanomolar inhibitory activity against PIM1 kinase and to inhibit the PIM1-mediated phosphorylation in cancer cells. We further determined the crystal complex structure of PIM1 bound with mitoxantrone, which reveals the structural and mechanistic basis for a novel mode of PIM1 inhibition. Although mitoxantrone's mechanism of action had been originally thought to act through DNA intercalation and type II topoisomerase inhibition, we hypothesize that PIM1 kinase inhibition might also contribute to mitoxantrone's therapeutic efficacy and specificity.
authors: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors: Xiaobo
authors: X
authors: Wan
authors: Wei
authors: W
authors: Zhang
authors: Li
authors: L
authors: Li
authors: Yuting
authors: Y
authors: Xie
authors: Wei
authors: W
authors: Li
authors: Niu
authors: N
authors: Huang
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D017277:Drug Approval; D005656:Fungal Proteins; D023281:Genomics; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D008942:Mitoxantrone; D020928:Mitogen-Activated Protein Kinases; C432694:Pim1 protein, Pichia pastoris