RRC ID 68581
著者 Nakano H, Saito N, Parker L, Tada Y, Abe M, Tsuganezawa K, Yokoyama S, Tanaka A, Kojima H, Okabe T, Nagano T.
タイトル 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.
ジャーナル J Med Chem
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.
巻・号 55(11)
ページ 5151-64
公開日 2012-6-14
DOI 10.1021/jm3001289
PMID 22540945
MeSH Antineoplastic Agents / chemical synthesis* Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Apoptosis / drug effects Aza Compounds / chemical synthesis* Aza Compounds / chemistry Aza Compounds / pharmacology Benzofurans / chemical synthesis* Benzofurans / chemistry Benzofurans / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Crystallography, X-Ray Databases, Factual Drug Screening Assays, Antitumor G1 Phase / drug effects Humans Indoles / chemical synthesis* Indoles / chemistry Indoles / pharmacology Leukemia Models, Molecular Molecular Structure Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors* Stereoisomerism Structure-Activity Relationship
IF 6.205
リソース情報
ヒト・動物細胞 WI-38(RCB0702)