Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound

Abstract

Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Aberrant Expression of Pim-3 Promotes Proliferation and Migration of Ovarian Cancer Cells

“…Moreover, in cancer patients, upregulation of Pim-3 expression level is significantly correlated with the FIGO stage (p<0.05), histopathological subtypes (p<0.05) and metastasis (p<0.05). Recently, several studies reported that Pim-3 could promote cancer invasion and metastasis in gastric and pancreatic cancer, sarcoma and other tumors (Nakano et al, 2012;Zhang et al, 2013;Lou et al, 2014). These findings regarding the role of Pim-3 in different cancers support the clinical results of our study, implying that Pim-3 may ubiquitously promote cancer invasion and metastasis.…”

“…And Pim-3 was also associated with sarcoma-induced bone invasion (NarlikGrassow et al, 2012). The inhibition of Pim-3 by shRNA also reduced endothelial cell spreading, vascular tube formation, and migration of prostate cancer (Nakano et al, 2012). Pim-3 can be regulated by the Ets family of transcription factors in NIH3T3 cells and human Ewing's sarcoma cells (Deneen et al, 2003).…”

Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor

“…We believe that inhibitors such as compound 1 (Fig. 3a) and its derivatives described in Nakano et al (2012) have the potential to be developed further. Compound 14, the most advanced of the series, inhibits the growth of the human leukaemia cell line MV4-11 (Nakano et al, 2012).…”

“…3a) and its derivatives described in Nakano et al (2012) have the potential to be developed further. Compound 14, the most advanced of the series, inhibits the growth of the human leukaemia cell line MV4-11 (Nakano et al, 2012). Like compound 1 and its derivatives, binding of 14 caused the P-loop to adopt a novel conformation.…”

“…Much attention has recently been focused on identifying potential Pim-1 inhibitor candidates for the treatment of haematopoietic malignancies. The outcome of a rational drug-design project has recently been reported [Nakano et al (2012), J. Med. Chem.…”