Zdravko V. Milanov
Ambit Biosciences
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Publication
Featured researches published by Zdravko V. Milanov.
Nature Biotechnology | 2008
Mazen W. Karaman; Sanna Herrgard; Daniel Kelly Treiber; Paul Gallant; Corey E. Atteridge; Brian T. Campbell; Katrina W Chan; Pietro Ciceri; Mindy I. Davis; Philip T. Edeen; Raffaella Faraoni; Mark Floyd; Jeremy P. Hunt; Daniel J Lockhart; Zdravko V. Milanov; Michael J Morrison; Gabriel Pallares; Hitesh K. Patel; Stephanie Pritchard; Lisa M. Wodicka; Patrick P. Zarrinkar
Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
Nature Biotechnology | 2005
Miles A. Fabian; William H. Biggs; Daniel Kelly Treiber; Corey E. Atteridge; Mihai Azimioara; Michael G Benedetti; Todd A. Carter; Pietro Ciceri; Philip T. Edeen; Mark Floyd; Julia M. Ford; Margaret Galvin; Jay L Gerlach; Robert M. Grotzfeld; Sanna Herrgard; Darren E. Insko; Michael A Insko; Andiliy G. Lai; Jean-Michel Lélias; Shamal A. Mehta; Zdravko V. Milanov; Anne Marie Velasco; Lisa M. Wodicka; Hitesh K. Patel; Patrick P. Zarrinkar; David J. Lockhart
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
Bioorganic & Medicinal Chemistry Letters | 2009
Hitesh K. Patel; Robert M. Grotzfeld; Andiliy G. Lai; Shamal A. Mehta; Zdravko V. Milanov; Qi Chao; Kelly G. Sprankle; Todd A. Carter; Anne Marie Velasco; Miles A. Fabian; Joyce James; Daniel Kelly Treiber; David J. Lockhart; Patrick P. Zarrinkar; Shripad S. Bhagwat
A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.
Bioorganic & Medicinal Chemistry Letters | 2011
Sunny Abraham; Michael J. Hadd; Lan Tran; Troy Vickers; Janice Sindac; Zdravko V. Milanov; Mark W. Holladay; Shripad S. Bhagwat; Helen Hua; Julia M. Ford Pulido; Merryl D. Cramer; Dana Gitnick; Joyce James; Alan Dao; Barbara Belli; Robert C. Armstrong; Daniel Kelly Treiber; Gang Liu
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.
Archive | 2005
Robert M. Grotzfeld; Hitesh K. Patel; Shamal A. Mehta; Zdravko V. Milanov; Andiliy G. Lai; David J. Lockhart
Archive | 2004
Zdravko V. Milanov; Hitesh K. Patel; Robert M. Grotzfeld; Shamal A. Mehta; Andiliy G. Lai; David J. Lockhart
Archive | 2004
Shamal A. Mehta; Robert M. Grotzfeld; Zdravko V. Milanov; Andiliy G. Lai; Hitesh K. Patel; David J. Lockhart
Archive | 2004
Robert M. Grotzfeld; Hitesh K. Patel; Shamal A. Mehta; Zdravko V. Milanov; Andiliy G. Lai; David J. Lockhart
Archive | 2004
Andiliy G. Lai; Shamal A. Mehta; Zdravko V. Milanov; Robert M. Grotzfeld; Hitesh K. Patel; David J. Lockhart
Archive | 2004
Shamal A. Mehta; Robert M. Grotzfeld; Zdravko V. Milanov; Andiliy G. Lai; Hitesh K. Patel; David J. Lockhart