Discovery and SAR of spirochromane Akt inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 8; pp. 2410 - 2414
• Main Authors: Kallan, Nicholas C., Spencer, Keith L., Blake, James F., Xu, Rui, Heizer, Justin, Bencsik, Josef R., Mitchell, Ian S., Gloor, Susan L., Martinson, Matthew, Risom, Tyler, Gross, Stefan D., Morales, Tony H., Wu, Wen-I, Vigers, Guy P.A., Brandhuber, Barbara J., Skelton, Nicholas J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.04.2011; Elsevier
• Subjects: Akt kinase inhibitors; Antineoplastic agents; Binding Sites; Biological and medical sciences; cAMP-dependent protein kinase; Crystallography, X-Ray; Drug Evaluation, Preclinical; enzyme inhibitors; General aspects; Medical sciences; Pharmacology. Drug treatments; phenol; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Structure-Activity Relationship; structure-activity relationships; Akt kinase inhibitors; Antineoplastic agent; Sulfonamide; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Benzene derivatives; Akt protein kinase; Enzyme inhibitor; Inhibitor enzyme complex; Selectivity; Tetracyclic compound; In vitro; Modeling; Signal transduction; Structure activity relation; Molecular model; Aromatic compound; Secondary alcohol; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.02.073

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. 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.