Pyrazolone-based anaplastic lymphoma kinase (ALK) inhibitors: Control of selectivity by a benzyloxy group

被引：26

作者：

Tripathy, Rabindranath ^{[1
]}

McHugh, Robert J. ^{[1
]}

Ghose, Arup K. ^{[1
]}

Ott, Gregory R. ^{[1
]}

Angeles, Thelma S. ^{[1
]}

Albom, Mark S. ^{[1
]}

Huang, Zeck ^{[1
]}

Aimone, Lisa D. ^{[1
]}

Cheng, Mangeng ^{[1
]}

Dorsey, Bruce D. ^{[1
]}

机构：

[1] Cephalon Inc, Worldwide Discovery Res, W Chester, PA 19380 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 24期

关键词：

ALK; NMP-ALK; ALCL; Pyrazolone; VEGFR2; IDENTIFICATION; CANCERS; BINDING; FUSION; POTENT; GENE; NPM;

D O I：

10.1016/j.bmcl.2011.10.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Anaplastic lymphoma kinase (ALK) is transmembrane receptor tyrosine kinase, with oncogenic variants that have been implicated in ALCL, NSCLC and other cancers. Screening of a VEGFR2-biased kinase library resulted in identification of 1 which showed cross-reactivity with ALK. SAR on the indole segment of 1 showed that a subtle structural modification (the ethoxy group of 1 changed to a benzyloxy to generate 5a) enhanced potency (ALK), selectivity for VEGFR2 and IR along with improvement in metabolic stability. From docking studies of ALK versus VEGFR2 kinase, we postulated that the loss of entropy of the VEGFR2 in the bound form with 5a might be the origin of the reduced activity against that protein. Modification of the heterocyclic segment showed that thiazole-bearing pyrazolones preserved enzyme potency, and enhanced inhibition of NPM-ALK autophosphorylation in ALK-positive ALCL cells (Karpas-299). SAR of the benzyloxy group resulted in compounds which demonstrated good cellular potency in Karpas-299 cells. Compound 8 showed best overall profile for the series with broad kinome selectivity and liver micorsome stability. Compound 8 showed reasonable iv PK in rat, but with little oral exposure. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：7261 / 7264

页数：4

共 27 条

[1]

Bhagwat SS, 2009, CURR OPIN INVEST DR, V10, P1266

[2] Small kinase assay panels can provide a measure of selectivity [J].

Brandt, Peter ;

Jensen, Annika Jenmalm ;

Nilsson, Jonas .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (20) :5861-5863

[3]

CHRISTENSEN JG, 2007, MOL CANC THER

[4] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

[5] Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK [J].

Galkin, Anna V. ;

Melnick, Jonathan S. ;

Kim, Sungjoon ;

Hood, Tami L. ;

Li, Nanxin ;

Li, Lintong ;

Xia, Gang ;

Steensma, Ruo ;

Chopiuk, Greg ;

Jiang, Jiqing ;

Wan, Yongqin ;

Ding, Peter ;

Liu, Yi ;

Sun, Fangxian ;

Schultz, Peter G. ;

Gray, Nathanael S. ;

Warmuth, Markus .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (01) :270-275

[6] Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery [J].

Ghose, Arup K. ;

Herbertz, Torsten ;

Pippin, Douglas A. ;

Salvino, Joseph M. ;

Mallamo, John P. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (17) :5149-5171

[7] Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors [J].

Kinoshita, Kazutomo ;

Ono, Yoshiyuki ;

Emura, Takashi ;

Asoh, Kohsuke ;

Furuichi, Noriyuki ;

Ito, Toshiya ;

Kawada, Hatsuo ;

Tanaka, Shota ;

Morikami, Kenji ;

Tsukaguchi, Toshiyuki ;

Sakamoto, Hiroshi ;

Tsukuda, Takuo ;

Oikawa, Nobuhiro .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (12) :3788-3793

[8] Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors [J].

Lovly, Christine M. ;

Heuckmann, Johannes M. ;

de Stanchina, Elisa ;

Chen, Heidi ;

Thomas, Roman K. ;

Liang, Chris ;

Pao, William .

CANCER RESEARCH, 2011, 71 (14) :4920-4931

[9] ALK Mutants in the Kinase Domain Exhibit Altered Kinase Activity and Differential Sensitivity to Small Molecule ALK Inhibitors [J].

Lu, Lihui ;

Ghose, Arup K. ;

Quail, Matthew R. ;

Albom, Mark S. ;

Durkin, John T. ;

Holskin, Beverly P. ;

Angeles, Thelma S. ;

Meyer, Sheryl L. ;

Ruggeri, Bruce A. ;

Cheng, Mangeng .

BIOCHEMISTRY, 2009, 48 (16) :3600-3609

[10]

MCHUGH RJ, 2008, 235 ACS NAT M APR

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