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Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

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.

SUBMITTER: Burger MT

PROVIDER: S-EPMC4027555 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

Burger Matthew T MT Han Wooseok W Lan Jiong J Nishiguchi Gisele G Bellamacina Cornelia C Lindval Mika M Atallah Gordana G Ding Yu Y Mathur Michelle M McBride Chris C Beans Elizabeth L EL Muller Kristine K Tamez Victoriano V Zhang Yanchen Y Huh Kay K Feucht Paul P Zavorotinskaya Tatiana T Dai Yumin Y Holash Jocelyn J Castillo Joseph J Langowski John J Wang Yingyun Y Chen Min Y MY Garcia Pablo D PD

ACS medicinal chemistry letters 20131015 12

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 struc ...[more]

PMID: 24900629

Dataset Information

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

Publications

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

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