Hydrophobic motifs

It will be interesting to see how compounds with such mechanisms may be optimised into clinical candidates over the coming years. One particular challenge of compounds exploiting largely hydrophobic regions may be the physicochemical and pharmaceutical properties of the inhibitors and how this may affect their pharmacokinetic (PK) properties in vivo. 

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Sequence-specific transcription factors often bind as multimers especially as dimers to DNA. This allows binding of mirror-imaged sequences (palindromes) in the DNA that are separated by a few spacer nucleotides. The dimerization is stabilized by hydrophobic motifs within dimerization motifs of each transcription factor molecule. Dependent on the nature of the dimerization domain and the abundance of individual transcription factors homo- or heterodimers can form and bind to palindromes with differential activity. 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

FIGURE 8.8 Mechanism of activation of protein kinase B (PKB). PI3-kinase is recruited to the membrane via direct association with the receptor PTK or via association with the docking protein Gab-1. It catalyzes the generation of phosphatidyl-3,4,5-inositolphosphate, which serves as a membrane-recruitment signal for PKB. Associated with the membrane, it is first phosphorylated in its catalytic domain by PDK1 and then by PDK2 in the hydrophobic motif. The activated PKB then detaches from the membrane. 

Protein kinase B (PKB), which is also known as Akt, is a serine/threonine kinase that also belongs to the AGC kinase subtype. Three mammalian isoforms—PKBo , /3, and y have been identified. These proteins are broadly expressed and, although isoform-specific patterns of expression exists in some tissues, the three kinases have a similar organizational structure an amino-terminal PH domain, a central serine/threonine catalytic domain, and a short regulatory region at the carboxy terminal end containing the so-called hydrophobic motif [118-120]. 

Constantinescu, S. N., Huang, L. J., Nam, H., and Lodish, H. F. (2001). The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol. Cell 7, 377-385. 

As shown in Fig. 3b, c, the phospho PDK docking motif antibody, very specifically detects the phosphorylation state of the hydrophobic motif of the PKBRl. This phosphorylation is completely absent in competent cells prior to stimulation. Following addition of cAMP, it increases rapidly, peaks at 30 s, and disappears within 2 min. This phosphorylation is completely absent in cells lacking PiaA and substantially decreased in cells lacking Rip3 (data not shown), indicating that it is a TorC2 substrate. 

The SAR in the P4-P3 linker region was further explored with a novel 0x0-linker macrocyclic series represented by compounds 59-64 (Table 7.7). Substituents incorporated into 59-64 were to a large degree based on the presumed preference for a hydrophobic motif in the P4-P3 position (with... 

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