Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

Converso, Antonella; Hartingh, Timothy J.; Garbaccio, R. M.; Tasber, Edward S.; Rickert, Keith; Fraley, Mark E.; Yan, Yong-Bin; Kreatsoulas, Constantine; Stirdivant, Steve; Drakas, Bob; Walsh, Eileen S.; Hamilton, Kelly; Buser, Carolyn A.; Mao, Xianzhi; Abrams, Marc; Beck, Steve; Tao, Weikang; Lobell, Rob; Sepp‐Lorenzino, Laura; Zugay-Murphy, Joan; Sardana, Vinod; Munshi, Sanjeev; Jezequel-Sur, Sylvie Marie; Zuck, Paul; Hartman, George D.

doi:10.1016/j.bmcl.2008.12.076

Cited by 72 publications

(50 citation statements)

References 17 publications

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“…The structurally resolved allosteric KIs known thus far include compounds that inhibit mitogen-activated protein kinase kinase, protein kinase B (AKT), or insulinlike growth factor 1 receptor by occupying a pocket adjacent to the ATP binding site ("allosteric back-pocket") (Ohren et al, 2004;Barnett et al, 2005;Lindsley et al, 2005) or bind to more remote sites, like the myristate binding site (Adrian et al, 2006;Zhang et al, 2009Zhang et al, , 2010, the rapamycin binding site of mTOR (Choi et al, 1996;Wang and Sun, 2009;Yang et al, 2013), or the peptide binding site recently discovered in checkpoint kinase 1 (Converso et al, 2009). In addition, targeting the allosteric sites on protein kinases may provide means to identify activators rather than inhibitors that could be useful for therapeutic intervention (Grimsby et al, 2003;Guertin and Grimsby, 2006;Sanders et al, 2007;Hindie et al, 2009).…”

Section: Nomenclature For Ligand-receptor Allosterymentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

et al. 2014

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Section: Nomenclature For Ligand-receptor Allosterymentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

et al. 2014

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“…Type 3 inhibitors that are further away from the ATP site are the myristate (myr) pocket binders located in the bottom of the C-lobe of ABL (Adrian et al, 2006;Zhang et al, 2009;Fabbro et al, 2010), CHK1 inhibitors that occupy, in part, the substrate-binding site (Converso et al, 2009), and JNK1 inhibitors that occupy the mitogen-activated protein kinase insert region and A-loop (Comess et al, 2011), to only cite a few. A more comprehensive review on type 3 inhibitors has at ASPET Journals on May 9, 2018 molpharm.aspetjournals.org…”

Section: Reversible (Noncovalent) Inhibitorsmentioning

confidence: 99%

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

2014

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Deregulation of protein and lipid kinase activities leads to a variety of pathologies, ranging from cancer inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders. Protein kinases and lipid kinases represent, therefore, an important target for the pharmaceutical industry. In fact, approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases. To date, 30 kinase inhibitors have been approved, which, with few exceptions, are mainly for oncological indications and directed against only a handful of protein and lipid kinases, leaving 70% of the kinome untapped. Despite these successes in kinase drug discovery, the development of kinase inhibitors with outstanding selectivity, identification and validation of driver kinase(s) in diseases, and the emerging problem of resistance to the inhibition of key target kinases remain major challenges. This minireview provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.

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“…Many research groups performed studies on the DFG-out conformation of kinases and developed type-II kinase inhibitors. [7][8][9][10][11][12][13][14][15][16][17] Previous reports indicated that allosteric binding pocket of p38 was used to find out potent molecules. This lead to discovery of potent allosteric inhibitor BIRB, currently in phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

Gadhe¹,

Balupuri²,

Kothandan³

et al. 2014

Bulletin of the Korean Chemical Society

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P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.

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Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

Cited by 72 publications

References 17 publications

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

Theoretical Characterization of Binding Mode of Organosilicon Inhibitor with p38: Docking, MD Simulation and MM/GBSA Free Energy Approach

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