- Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2
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Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.
- Heightman, Tom D.,Berdini, Valerio,Braithwaite, Hannah,Buck, Ildiko M.,Cassidy, Megan,Castro, Juan,Courtin, Aurélie,Day, James E. H.,East, Charlotte,Fazal, Lynsey,Graham, Brent,Griffiths-Jones, Charlotte M.,Lyons, John F.,Martins, Vanessa,Muench, Sandra,Munck, Joanne M.,Norton, David,O'Reilly, Marc,Palmer, Nick,Pathuri, Puja,Reader, Michael,Rees, David C.,Rich, Sharna J.,Richardson, Caroline,Saini, Harpreet,Thompson, Neil T.,Wallis, Nicola G.,Walton, Hugh,Wilsher, Nicola E.,Woolford, Alison J.-A.,Cooke, Michael,Cousin, David,Onions, Stuart,Shannon, Jonathan,Watts, John,Murray, Christopher W.
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- Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design
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Constitutive activation of MAPK (RAS/RAF/MEK/ERK) pathway is frequently observed in many tumors and thus has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Inspired by the central role of the ERK1/2 signaling cascade in cancer, we describe the scaffold-hopping generation of a series of isoindolin-1-one ERK1/2 inhibitors. Our new compounds could inhibit proliferation of KRAS and BRAF mutant cells lines at low nanomolar concentrations. Compound 22a possesses acceptable pharmacokinetic profiles and showed considerable in vivo antitumor efficacy in a HCT-116 xenograft model, providing a promising basis for further optimization towards clinical ERK1/2 inhibitors.
- Ji, Dezhong,Zhang, Lingzhi,Zhu, Qihua,Bai, Ying,Wu, Yaoyao,Xu, Yungen
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- 3-(1H-PYRAZOL-4-YL)PYRIDINE ALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR
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The present invention is directed to pyrazol-4-yl-pyridine compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.
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Page/Page column 72-73; 75
(2019/01/16)
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- ASK1 INHIBITOR COMPOUNDS AND USES THEREOF
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Described herein are compounds, including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat non
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Paragraph 0431
(2018/11/02)
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- 3- (1H-PYRAZOL-4-YL) PYRIDINEALLOSTERIC MODULATORS OF THE M4 MUSCARINIC ACETYLCHOLINE RECEPTOR
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The present invention is directed to pyrazol-4-yl-pyridine compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.
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Page/Page column 37; 38
(2017/07/14)
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- BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.
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Page/Page column 208; 209
(2017/08/01)
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- IMIDAZOPYRIDAZINE DERIVATIVES AS MODULATORS OF THE GABAA RECEPTOR ACTIVITY.
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The present invention relates to imidazopyridazine derivatives. More particularly, it relates to 4-(biphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine derivatives of formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R and R6 are as defined in the description. The imidazopyridazine derivatives of the present invention modulate the activity of the GABAA receptor. They are useful in the treatment of a number of conditions, including pain.
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- Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin
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A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1-1.2 h (dose of 5 mg/kg iv) and MTDs of 60-80 mg/kg (ip).
- Spicer, Julie A.,Lena, Gersande,Lyons, Dani M.,Huttunen, Kristiina M.,Miller, Christian K.,O'Connor, Patrick D.,Bull, Matthew,Helsby, Nuala,Jamieson, Stephen M. F.,Denny, William A.,Ciccone, Annette,Browne, Kylie A.,Lopez, Jamie A.,Rudd-Schmidt, Jesse,Voskoboinik, Ilia,Trapani, Joseph A.
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supporting information
p. 9542 - 9555
(2014/01/06)
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- NOVEL COMPOUNDS AS MODULATORS OF PROTEIN KINASES
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The present invention provides PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.
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Page/Page column 128; 129
(2012/11/14)
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- MODULATORS OF ATP-BINDING CASSETTE-TRANSPORTERS
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Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (""ABC"") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (""CFTR""). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
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- 2-METHYLMORPHOLINE PYRIDO-, PYRAZO- AND PYRIMIDO-PYRIMIDINE DERIVATIVES AS MTOR INHIBITORS
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There is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula (1), and the use of a compound of Formula (1) as a medicament and in the treatment of cancer
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Page/Page column 117
(2008/06/13)
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