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

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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.

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