A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling.

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Wan X, Zhang W, Li L, Xie Y, Li W, Huang N

A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling.

J Med Chem. 2013 Mar 28;56(6):2619-29. doi: 10.1021/jm400045y. Epub 2013 Mar 15.

PubMed ID

23442188 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Neflamapimod	Mitogen-activated protein kinase 14	Kd (nM)	2.8	N/A	N/A	Details