Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode.

A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection-mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.

[1]  K. Arrington,et al.  Novel Inhibitors of Checkpoint Kinase 1 , 2007, ChemMedChem.

[2]  J. McCarter,et al.  Inhibitors of the lipid phosphatase SHIP2 discovered by high-throughput affinity selection-mass spectrometry screening of combinatorial libraries. , 2009, Combinatorial chemistry & high throughput screening.

[3]  Caterina Barillari,et al.  Classification of water molecules in protein binding sites. , 2007, Journal of the American Chemical Society.

[4]  R. Schlegel,et al.  Suppression of Apoptosis by Dominant Negative Mutants of Cyclin-dependent Protein Kinases (*) , 1996, The Journal of Biological Chemistry.

[5]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[6]  C. Chuang,et al.  ALIS: An Affinity Selection–Mass Spectrometry System for the Discovery and Characterization of Protein–Ligand Interactions , 2007 .

[7]  B. Kuhn,et al.  Intramolecular hydrogen bonding in medicinal chemistry. , 2010, Journal of medicinal chemistry.

[8]  P. O'Connor,et al.  Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1 , 2008, Molecular Cancer Therapeutics.

[9]  M. McCoy,et al.  Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors. , 2011, ACS medicinal chemistry letters.

[10]  S. Buchwald,et al.  A highly active catalyst for Suzuki-Miyaura cross-coupling reactions of heteroaryl compounds. , 2006, Angewandte Chemie.

[11]  W. Seghezzi,et al.  Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[12]  G. Bemis,et al.  Kinase inhibitors and the case for CH…O hydrogen bonds in protein–ligand binding , 2002, Proteins.

[13]  Laurence H. Hurley,et al.  DNA and its associated processes as targets for cancer therapy , 2002, Nature Reviews Cancer.

[14]  W. Seghezzi,et al.  Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening , 2011, Molecular Cancer Therapeutics.

[15]  Patrick J. Curran,et al.  Aminothiazole inhibitors of HCV RNA polymerase. , 2005, Bioorganic & medicinal chemistry letters.

[16]  Stephen L. Buchwald,et al.  Efficient Palladium‐Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction. , 2004 .

[17]  Patrick J. Curran,et al.  An affinity selection–mass spectrometry method for the identification of small molecule ligands from self-encoded combinatorial libraries: Discovery of a novel antagonist of E. coli dihydrofolate reductase , 2004 .

[18]  A. Gunasekera,et al.  Chk 1 Mediates S and G 2 Arrests through Cdc 25 A Degradation in Response to DNA-damaging Agents * , 2003 .

[19]  D. A. Annis,et al.  A general technique to rank protein-ligand binding affinities and determine allosteric versus direct binding site competition in compound mixtures. , 2004, Journal of the American Chemical Society.

[20]  T. Kowalski,et al.  Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity , 2011, Journal of Lipid Research.

[21]  A. Gunasekera,et al.  Chk1 Mediates S and G2 Arrests through Cdc25A Degradation in Response to DNA-damaging Agents* , 2003, Journal of Biological Chemistry.

[22]  Patrick J. Curran,et al.  The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[23]  T. Kawabe.  G2 checkpoint abrogators as anticancer drugs. , 2004, Molecular cancer therapeutics.

[24]  Patrick J. Curran,et al.  Method for quantitative protein-ligand affinity measurements in compound mixtures. , 2007, Analytical chemistry.

[25]  Zhiwei Yang,et al.  Discovery and optimization of antibacterial AccC inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[26]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[27]  D. Parry,et al.  Chk1 is Essential for Tumor Cell Viability Following Activation of the Replication Checkpoint , 2005, Cell cycle.

[28]  Stephen Green,et al.  AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies , 2008, Molecular Cancer Therapeutics.

[29]  Sony Agrawal,et al.  Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides. , 2010, Bioorganic & medicinal chemistry letters.

[30]  W. Plunkett,et al.  Inhibition of cyclin-dependent kinase 2 by the Chk1-Cdc25A pathway during the S-phase checkpoint activated by fludarabine: dysregulation by 7-hydroxystaurosporine. , 2002, Molecular pharmacology.

[31]  Michael R. Ziebell,et al.  Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection-Mass Spectrometry , 2006, Journal of biomolecular screening.

[32]  J. Janetka,et al.  Keeping checkpoint kinases in line: new selective inhibitors in clinical trials. , 2008, Expert opinion on investigational drugs.

[33]  T. Fischmann,et al.  Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2. , 2011, Bioorganic & medicinal chemistry letters.

[34]  Protein–Ligand Interactions. Methods and Principles in Medicinal Chemistry Series, Volume 53. Edited by Holger Gohlke. , 2013 .