717907-76-1Relevant academic research and scientific papers
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
Berger, Benedict-Tilman,Amaral, Marta,Kokh, Daria B.,Nunes-Alves, Ariane,Musil, Djordje,Heinrich, Timo,Schr?der, Martin,Neil, Rebecca,Wang, Jing,Navratilova, Iva,Bomke, Joerg,Elkins, Jonathan M.,Müller, Susanne,Frech, Matthias,Wade, Rebecca C.,Knapp, Stefan
, p. 686 - 7,698 (2021/02/16)
There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.
PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF ABNORMAL CELL GROWTH
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Page/Page column 8, (2011/02/26)
The present invention relates to salts, solvates and substoichiometric solvates of N-[3-[[[2-[(2,3-dihydro-2-oxo-1H-indo1-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]-N-methylmethanesulfonamide. The invention also provides pharmaceutical compositions comprising such complexes, as well as methods of treating abnormal cell growth by administering the complexes of the invention.
Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure-activity relationships and strategies for the elimination of reactive metabolite formation
Walker, Daniel P.,Christopher Bi,Kalgutkar, Amit S.,Bauman, Jonathan N.,Zhao, Sabrina X.,Soglia, John R.,Aspnes, Gary E.,Kung, Daniel W.,Klug-McLeod, Jacquelyn,Zawistoski, Michael P.,McGlynn, Molly A.,Oliver, Robert,Dunn, Matthew,Li, Jian-Cheng,Richter, Daniel T.,Cooper, Beth A.,Kath, John C.,Hulford, Catherine A.,Autry, Christopher L.,Luzzio, Michael J.,Ung, Ethan J.,Roberts, W. Gregory,Bonnette, Peter C.,Buckbinder, Leonard,Mistry, Anil,Griffor, Matthew C.,Han, Seungil,Guzman-Perez, Angel
scheme or table, p. 6071 - 6077 (2009/08/07)
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Pyrimidine derivatives for the treatment of abnormal cell growth
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Page/Page column 20, (2010/02/14)
The present invention relates to a compound of the formula 1 wherein A and Ar are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Pyrimidine derivatives for the treatment of abnormal cell growth
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Page/Page column 35; 43, (2008/06/13)
The present invention relates to a compound of the formula 1 wherein R1-R4 are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
SELECTIVE SYNTHESIS OF CF3-SUBSTITUTED PYRIMIDINES
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Page/Page column 10, (2008/06/13)
The present invention relates to a method of making a compound of the formula (I),wherein X1, X2 and R3-R4 are as defined herein. The method includes reacting a compound of the formula (II) with an amine of formula (III) (HNR33R44) in the presence of a Lewis Acid and a non-nucleophilic base. The 2,4-diamino pyrimidine moiety is a common component in a variety of biologically active drug-like molecules and pyrimidine derivatives have been found to be useful in the 10 treatment of abnormal cell growth, such as cancer, in mammals.
