| Literature DB >> 24900629 |
Matthew T Burger1, Wooseok Han1, Jiong Lan1, Gisele Nishiguchi1, Cornelia Bellamacina1, Mika Lindval1, Gordana Atallah1, Yu Ding1, Michelle Mathur1, Chris McBride1, Elizabeth L Beans1, Kristine Muller1, Victoriano Tamez1, Yanchen Zhang1, Kay Huh1, Paul Feucht2, Tatiana Zavorotinskaya2, Yumin Dai2, Jocelyn Holash2, Joseph Castillo2, John Langowski2, Yingyun Wang2, Min Y Chen2, Pablo D Garcia2.
Abstract
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.Entities:
Keywords: Pim1 kinase inhibitor; Pim2 kinase inhibitor; Pim3 kinase inhibitor; Proviral insetion site in Moloney murine leukemia virus kinases inhibitors; pan-Pim kinase inhibitors
Year: 2013 PMID： 24900629 PMCID： PMC4027555 DOI： 10.1021/ml400307j
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345