- De-novo designed library of benzoylureas as inhibitors of BCL-X L: Synthesis, structural and biochemical characterization
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The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
- Brady, Ryan M.,Vom, Amelia,Roy, Michael J.,Toovey, Nathan,Smith, Brian J.,Moss, Rebecca M.,Hatzis, Effie,Huang, David C. S.,Parisot, John P.,Yang, Hong,Street, Ian P.,Colman, Peter M.,Czabotar, Peter E.,Baell, Jonathan B.,Lessene, Guillaume
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p. 1323 - 1343
(2014/03/21)
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- Targeting the heat shock protein 90 dimer with dimeric inhibitors
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The design, synthesis, and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3 mm2, A549, and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent antiproliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ü100 fold increase in antiproliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
- Kusuma, Bhaskar Reddy,Peterson, Laura B.,Zhao, Huiping,Vielhauer, George,Holzbeierlein, Jeffrey,Blagg, Brian S. J.
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scheme or table
p. 6234 - 6253
(2011/10/31)
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- Macrocyclic Compounds Useful as Bace Inhibitors
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The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 30
(2008/12/05)
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- Alpha-helical mimetics
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Benzoyl urea derivatives that are alpha helical peptides mimetics that mimic BH3-only proteins, compositions containing them, their conjugation to cell-targeting-moieties, and their use in the regulation of cell death are disclosed. The benzoyl urea derivatives are capable of binding to and neutralizing pro-survival Bcl-2 proteins. Use of benzoyl urea derivatives in the treatment and/or prophylaxis of diseases or conditions associated with deregulation of cell death are also described.
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Page/Page column 91
(2011/05/18)
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- ALPHA-HELICAL MIMETICS
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Benzoyl urea derivatives that are alpha helical peptide mimetics that mimic BH3-only proteins, compositions containing them, their conjugation to cell-targeting moieties, and their use in the regulation of cell death are disclosed. The benzoyl urea derivatives are capable of binding to and neutralising pro-survival Bcl-2 proteins. Use of the benzoyl urea derivatives in the treatment and/or prophylaxis of diseases or conditions associated with deregulation of cell death are also disclosed.
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Page/Page column 185
(2010/02/15)
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- The conversion of phenols to the corresponding aryl halides under mild conditions
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Mild, novel procedures have been developed for the syntheses of aryl halides from the corresponding phenols in modest to good yields via boronate ester intermediates.
- Thompson, Alicia L. S.,Kabalka, George W.,Akula, Murthy R.,Huffman, John W.
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p. 547 - 550
(2007/10/03)
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- A complementary method to obtain N-acyl enamides using the Heck reaction: Extending the substrate scope for asymmetric hydrogenation
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A series of N-acyl enamides were prepared using the Heck reaction. Asymmetric hydrogenation provided protected amines in up to 99% ee. A method to prepare N-acyl enamides is reported that is complementary to the existing protocols. Heck reaction of a vari
- Harrison, Paul,Meek, Graham
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p. 9277 - 9280
(2007/10/03)
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- NITROSODIPHENYLAMINE DERIVATIVES AND THEIR PHARMACEUTICAL USE AGAINST OXIDATIVE STRESS PATHOLOGIES
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Compounds of formula (I) in which each of the phenyl rings represented is optionally substituted one or more times; n represents an integer selected from 0, 1, 2, 3, 4 and 5; W represents -CO-or -SO2-; Z represents H; alkyl; aryl; or arylalkyl;
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Page/Page column 36
(2010/02/07)
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for improving cognitive function.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the prevention of atheroma progression and the regression of atheroma.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the treatment of angina.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the treatment of haemorrhagic stroke.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for primary and secondary prevention of infarction.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the treatment of diabetic nephropathy.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the treatment of macular degeneration.
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the treatment of left ventricular hypertrophy regression.
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- ANGIOTENSIN II RECEPTOR BLOCKING COMPOSITIONS
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This invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, an angiotensin II receptor antagonist and a second agent selected from a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibit
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- Medicament
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The present invention relates to the use of an angiotensin II receptor antagonist in the manufacture of a medicament for the primary and secondary prevention of infarction.
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