TY - JOUR
T1 - Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family
AU - Quevedo, Camilo E.
AU - J. R. Bataille, Carole
AU - Byrne, Simon
AU - Durbin, Matthew
AU - Elkins, Jon
AU - Guillermo, Abigail
AU - Jones, Alan M.
AU - Knapp, Stefan
AU - Nadali, Anna
AU - Walker, Roderick G.
AU - Wilkinson, Isabel
AU - Wynne, Graham M.
AU - Davies, Stephen G.
AU - Russell, Angela J.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.
AB - We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.
UR - http://www.scopus.com/inward/record.url?scp=85094625784&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2020.115724
DO - 10.1016/j.bmc.2020.115724
M3 - Article
SN - 0968-0896
VL - 28
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 22
M1 - 115724
ER -