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

被引：67

作者：

Nakano, Hirofumi ^{[2
]}

Saito, Nae ^{[2
]}

Parker, Lorien ^{[3
]}

Tada, Yukio ^{[2
]}

Abe, Masanao ^{[2
]}

Tsuganezawa, Keiko ^{[3
]}

Yokoyama, Shigeyuki ^{[3
,4
,5
]}

Tanaka, Akiko ^{[2
,3
]}

Kojima, Hirotatsu ^{[2
]}

Okabe, Takayoshi ^{[2
]}

Nagano, Tetsuo ^{[1
,2
]}

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[2] Univ Tokyo, Open Innovat Ctr Drug Discovery, Bunkyo Ku, Tokyo 1130033, Japan

[3] RIKEN Syst & Struct Biol Ctr, Yokohama, Kanagawa 2300045, Japan

[4] Univ Tokyo, Struct Biol Lab, Bunkyo Ku, Tokyo 1130033, Japan

[5] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Bunkyo Ku, Tokyo 1130033, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 11期

基金：

英国医学研究理事会;

关键词：

C-MYC; SERINE/THREONINE KINASES; PROTOONCOGENE PIM-1; STRUCTURAL BASIS; DECISION-MAKING; PROTEIN; DISCOVERY; PHOSPHORYLATES; IDENTIFICATION; PHOSPHATASE;

D O I：

10.1021/jm3001289

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 MV411 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.

引用

页码：5151 / 5164

页数：14

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