title: 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.
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Gisele
authors.initials: G
authors.lastname: Nishiguchi
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Bellamacina
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Mika
authors.initials: M
authors.lastname: Lindval
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Gordana
authors.initials: G
authors.lastname: Atallah
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mathur
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: McBride
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Beans
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Muller
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Victoriano
authors.initials: V
authors.lastname: Tamez
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yanchen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kay
authors.initials: K
authors.lastname: Huh
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Feucht
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Zavorotinskaya
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Castillo
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: John
authors.initials: J
authors.lastname: Langowski
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yingyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Min Y
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Oncology Research, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Garcia
keywords: Pim1 kinase inhibitor; Pim2 kinase inhibitor; Pim3 kinase inhibitor; Proviral insetion site in Moloney murine leukemia virus kinases inhibitors; pan-Pim kinase inhibitors