sgi-1776 and Leukemia

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.

Topics: Antineoplastic Agents; Apoptosis; Aza Compounds; Benzofurans; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Databases, Factual; Drug Screening Assays, Antitumor; G1 Phase; Humans; Indoles; Leukemia; Models, Molecular; Molecular Structure; Proto-Oncogene Proteins c-pim-1; Stereoisomerism; Structure-Activity Relationship