Analysis of Kinase Inhibitor Selectivity using a Thermodynamics-Based Partition Index

被引：41

作者：

Cheng, Alan C. ^{[1
]}

Eksterowicz, John ^{[3
]}

Geuns-Meyer, Stephanie ^{[2
]}

Sun, Yaxiong ^{[4
]}

机构：

[1] Amgen Inc, Mol Struct Dept, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Med Chem, Cambridge, MA 02142 USA

[3] Amgen Inc, Mol Struct Dept, San Francisco, CA 94080 USA

[4] Amgen Inc, Mol Struct Dept, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 11期

关键词：

GROWTH-FACTOR RECEPTOR; INTERACTION MAP; POTENT; FAMILY;

D O I：

10.1021/jm100301x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In the quest for safe, efficacious kinase inhibitors as drugs, selectivity is often assessed early using kinase profiling panels. Here we present a selectivity index based on thermodynamics principles that can help in analysis of the resulting data. The "partition" selectivity index is easy to calculate and is applicable in certain situations where other widely used indices are not. It is uniquely useful in analysis of small, focused selectivity panel data frequently encountered in medicinal chemistry hit-to-lead and lead optimization. For larger "kinome" panels, the partition index allows assessment of selectivity relative to a kinase or multiple kinases of interest.

引用

页码：4502 / 4510

页数：9

共 22 条

[1] Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase [J].

Cee, Victor J. ;

Cheng, Alan C. ;

Romero, Karina ;

Bellon, Steve ;

Mohr, Christopher ;

Whittington, Douglas A. ;

Bak, Annette ;

Bready, James ;

Caenepeel, Sean ;

Coxon, Angela ;

Deak, Holly L. ;

Fretland, Jenne ;

Gu, Yan ;

Hodous, Brian L. ;

Huang, Xin ;

Kim, Joseph L. ;

Lin, Jasmine ;

Long, Alexander M. ;

Nguyen, Hanh ;

Olivieri, Philip R. ;

Patel, Vinod F. ;

Wang, Ling ;

Zhou, Yihong ;

Hughes, Paul ;

Geuns-Meyer, Stephanie .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (02) :424-427

[2] Genetic interactions between Drosophila melanogaster Atg1and paxillin reveal a role for paxillin in autophagosome formation [J].

Chen, Guang-Chao ;

Lee, Janice Y. ;

Tang, Hong-Wen ;

Debnath, Jayanta ;

Thomas, Sheila M. ;

Settleman, Jeffrey .

AUTOPHAGY, 2008, 4 (01) :37-45

[3] Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580 [J].

Conway, JG ;

McDonald, B ;

Parham, J ;

Keith, B ;

Rusnak, DW ;

Shaw, E ;

Jansen, M ;

Lin, PY ;

Payne, A ;

Crosby, RM ;

Johnson, JH ;

Frick, L ;

Lin, MHJ ;

Depee, S ;

Tadepalli, S ;

Votta, B ;

James, I ;

Fuller, K ;

Chambers, TJ ;

Kull, FC ;

Chamberlain, SD ;

Hutchins, JT .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (44) :16078-16083

[4]

Dill K., 2002, Molecular Driving Forces: Statistical Thermodynamics in Chemistry Biology

[5] 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

[6] A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases [J].

Fedorov, Oleg ;

Marsden, Brian ;

Pogacic, Vanda ;

Rellos, Peter ;

Mueller, Susanne ;

Bullock, Alex N. ;

Schwaller, Juerg ;

Sundstrom, Michael ;

Knapp, Stefan .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (51) :20523-20528

[7] Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity [J].

Fitzgerald, CE ;

Patel, SB ;

Becker, JW ;

Cameron, PM ;

Zaller, D ;

Pikounis, VB ;

O'Keefe, SJ ;

Scapin, G .

NATURE STRUCTURAL BIOLOGY, 2003, 10 (09) :764-769

[8] Gini coefficient: A new way to express selectivity of kinase inhibitors against a family of kinases [J].

Graczyk, Piotr P. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (23) :5773-5779

[9] Synthesis and biological evaluation of pyrido[3′,2':4,5]furo [3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors [J].

Hayakawa, Masahiko ;

Kaizawa, Hiroyuki ;

Moritomo, Hiroyuki ;

Koizumi, Tomonobu ;

Ohishi, Takahide ;

Yamano, Mayumi ;

Okada, Minoru ;

Ohta, Mitsuaki ;

Tsukamoto, Shin-ichi ;

Raynaud, Florence I. ;

Workman, Paul ;

Waterfield, Michael D. ;

Parker, Peter .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (09) :2438-2442

[10] SB-431542 is a potent and specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7 [J].

Inman, GJ ;

Nicolás, FJ ;

Callahan, JF ;

Harling, JD ;

Gaster, LM ;

Reith, AD ;

Laping, NJ ;

Hill, CS .

MOLECULAR PHARMACOLOGY, 2002, 62 (01) :65-74

← 1 2 3 →