Target family prototype

Many non-receptor tyrosine kinases have been identified as products of retrovirally encoded oncogenes. Non-receptor tyrosine kinases can be divided into two groups transmembrane and cytosolic families. The c-src tyrosine kinase is the prototype of the cytosolic tyrosine kinases. Regions within these non-receptor tyrosine kinases share homology with the Src kinase, known as Src homology 2 and 3 (SH2 and SH3) domains, and mediate protein-protein interactions between the receptor tyrosine kinases and the intracellular targets (reviewed in Cantley et al., 1991 Pawson and Gish, 1992 Mayer and Baltimore, 1993). 

Neuronal survival and differentiation are regulated by many factors including neurotrophins and the Trk family of RPTKs. The prototype neurotrophin, nerve growth factor (NGF), promotes the survival of neurons during a period of programmed cell death in embryonic and early postnatal developmental stages. It is a target-derived neurotrophic factor that modulates the functions of the... 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

The sulfonylurea herbicides are a new family of chemical compounds, some of which are selectively toxic to weeds but not to crops. The selectivity of the sulfonylureas results from their metabolism to non-toxic compounds by particular crops, but not by weeds. In addition to efficient weed control, the sulfonylurea herbicides provide environmentally desirable properties such as field use rates as low as two grams/hectare and very low toxicity to mammals. The high specificity of the herbicides for their molecular target contributes to both of these properties. In addition, the low toxicity to mammals results from their lack of the target enzyme for the herbicides. Sulfonylureas inhibit the enzyme acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS), which catalyzes the first common step in the biosynthesis of the branched chain amino acids leucine, isoleucine and valine. In mammals these are three of the essential amino acids which must be obtained through dietary intake because the biosynthetic pathway for the branched chain amino acids is not present. The prototype structure of a sulfonylurea herbicide is shown in Figure 1. 

FK506-binding proteins (FKBP), a family of peptidyl prolyl cis/trans isomerases. FKBP are cellular targets of the macro-cyclic lactam FK506. Beside the prototypic FKBP12, up to 15 additional FKBP with higher molecular masses constitute the... 

The prototype compound of this family was the thymine derivative TSAO-T (Figure 2.18). TSAO derivatives were targeted at the HIV-l-encoded reverse transcriptase (RT) with which they interacted at a nonsubstrate binding site. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the TSAO nucleosides occupy a unique position in that they interfered at the interface between the P51 and P66 subunits of RT. A variety of 1,2,3-triazole TSAO derivatives (Figure 2.18) substituted at the 5-position of the triazole moiety were evaluated for their inhibitory effects against HIV-1- and HIV-2-induced cytopathicity in CEM and MT-4 cell cultures. The most active TSAO derivatives were those that contained either iV-ethyl (55) Af-cyclopropyl carbamoyl (56)... 

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