1 research outputs found
Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors
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 <i>K</i><sub>i</sub>s <
10 pM, nanomolar cellular potency, and in vivo activity in an acute
myeloid leukemia Pim-dependent tumor model is described