Search

Your search keyword '"Spencer, Keith L."' showing total 5 results
Start Over Author "Spencer, Keith L." Publisher elsevier science ltd
5 results on '"Spencer, Keith L."'

1. Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.

Author

Xu R, Banka A, Blake JF, Mitchell IS, Wallace EM, Bencsik JR, Kallan NC, Spencer KL, Gloor SL, Martinson M, Risom T, Gross SD, Morales TH, Wu WI, Vigers GP, Brandhuber BJ, and Skelton NJ

Subjects
Binding Sites, Computer Simulation, Crystallography, X-Ray, Cyclic AMP-Dependent Protein Kinases metabolism, Drug Evaluation, Preclinical, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides pharmacology, Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Spiro Compounds chemistry, Sulfonamides chemistry
Abstract

We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
Full Text
View/download PDF

2. Discovery and SAR of spirochromane Akt inhibitors.

Author

Kallan NC, Spencer KL, Blake JF, Xu R, Heizer J, Bencsik JR, Mitchell IS, Gloor SL, Martinson M, Risom T, Gross SD, Morales TH, Wu WI, Vigers GP, Brandhuber BJ, and Skelton NJ

Subjects
Binding Sites, Crystallography, X-Ray, Drug Evaluation, Preclinical, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Structure-Activity Relationship, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt antagonists & inhibitors
Abstract

A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
Full Text
View/download PDF

3. Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.

Author

Bencsik JR, Xiao D, Blake JF, Kallan NC, Mitchell IS, Spencer KL, Xu R, Gloor SL, Martinson M, Risom T, Woessner RD, Dizon F, Wu WI, Vigers GP, Brandhuber BJ, Skelton NJ, Prior WW, and Murray LJ

Subjects
Animals, Binding Sites, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Mice, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Structure-Activity Relationship, Tumor Burden drug effects, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyrimidines chemistry
Abstract

Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2010
Full Text
View/download PDF

4. Discovery of pyrrolopyrimidine inhibitors of Akt.

Author

Blake JF, Kallan NC, Xiao D, Xu R, Bencsik JR, Skelton NJ, Spencer KL, Mitchell IS, Woessner RD, Gloor SL, Risom T, Gross SD, Martinson M, Morales TH, Vigers GP, and Brandhuber BJ

Subjects
Adaptor Proteins, Signal Transducing, Animals, Binding Sites, Cell Line, Crystallography, X-Ray, Drug Design, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Mice, Phosphoproteins deficiency, Phosphoproteins genetics, Phosphoproteins metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt metabolism, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Pyrroles chemical synthesis, Pyrroles pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyrimidines chemistry, Pyrroles chemistry
Abstract

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2010
Full Text
View/download PDF

5. 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.

Author

Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, and Kreatsoulas C

Subjects
Cell Cycle drug effects, Cell Line, Tumor, Checkpoint Kinase 1, Crystallography, X-Ray, Humans, Indazoles metabolism, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors metabolism, Structure-Activity Relationship, Indazoles chemistry, Indazoles pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Protein Kinases metabolism
Abstract

The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.

Published
2006
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results