The Transition from a Pharmacophore-Guided Approach to a Receptor-Guided Approach in the Design of Potent Protein Kinase C Ligands

• Published in: Pharmacology & therapeutics (Oxford) Vol. 82; no. 2; pp. 251 - 261
• Main Authors: Marquez, Victor E, Nacro, Kassoum, Benzaria, Samira, Lee, Jeewoo, Sharma, Ravij, Teng, Kelly, Milne, George W.A, Bienfait, Bruno, Wang, Shaomeng, Lewin, Nancy E, Blumberg, Peter M
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.05.1999
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; diacylglycerol; diacylglycerol lactones; Drug Evaluation, Preclinical; Forecasting; Humans; In Vitro Techniques; Isoenzymes - chemistry; Isoenzymes - therapeutic use; Ligands; Neoplasms - drug therapy; Pharmacology - trends; PKC activation; PKC binding; PKC isozymes; Protein kinase C (PKC); Protein Kinase C - metabolism; Protein Kinases - metabolism; PMA, phorbol-12-myristate-13-acetate; PKC isozymes; PKC, protein kinase C; diacylglycerol lactones; DAG, diacylglycerol; PKC binding; PDBU, phorbol 12,13-dibutyrate; diacylglycerol; Protein kinase C (PKC); PKC activation
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/S0163-7258(98)00048-5

The pharmacophore-guided approach used in the first phase of the design of novel protein kinase C (PKC) ligands was based on the study of the geometry of bioequivalent pharmacophores present in diacylglycerol (DAG) and in the more potent phorbol ester tumor promoters. A number of potent DAG lactones were generated by this approach, in which the glycerol backbone was constrained into various heterocyclic rings to reduce the entropic penalty associated with DAG binding. Based on the information provided by X-ray and NMR structures of the cysteine-rich, C1 phorbol ester/DAG binding domain, the DAG lactones were further modified to optimize their interaction with a group of highly conserved hydrophobic amino acids along the rim of the C1 domain. This receptor-guided approach culminated with the synthesis of a series of “super DAG” molecules that can bind to PKC with low nanomolar affinities. These compounds provide insight into the basis for PKC ligand specificity. Moreover, some of the compounds reviewed herein show potential utility as antitumor agents.