Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 22; p. 115724
• Main Authors: Quevedo, Camilo E., Bataille, Carole J.R., Byrne, Simon, Durbin, Matthew, Elkins, Jon, Guillermo, Abigail, Jones, Alan M., Knapp, Stefan, Nadali, Anna, Walker, Roderick G., Wilkinson, Isabel V.L., Wynne, Graham M., Davies, Stephen G., Russell, Angela J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2020; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; REGULATOR; PHOSPHORYLATION; FLT3; GROWTH; AZD1208; LEUKEMIA; REPRESSOR; EXPRESSION; DISCOVERY; PHAS-I
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115724

[Display omitted] 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.