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inhibitors [73–75,82,83] and, more recently, a novel non-Cys containing peptide inhibitors [76,84] have
led to potent and cellularly active compounds. As illustrated in Figure 15, the “collected” substratebased
inhibitor 70 was designed to covalently attach farnesyl to a peptide via a phosphinic acid linker
replacement for [82], and this compound has been determined to be both potent against the target
enzyme and cellularly effective. Relative to peptide substrate structure-based design efforts,
peptidomimetics incorporating Ψ[CH 2NH]-substitutions (e.g., 62, [73]) or a benzodiazepinone
replacement of the central dipeptide moiety (e.g., 63, [74]) have yielded high affinity inhibitors. Another
series of very potent Ras farnesyl transferase inhibitors have been designed in which the central
dipeptide has been substituted by various isomeric and/or homologated derivatives of amino benzoic
acid (e.g., 64 [75]), including a particularly effective analog biphenyl derivative 71 [83]. The above
studies indicated that both conformationally flexible or constrained peptide scaffolds as well as
nonpeptide template replacements can be used to “link” the Cys and Met substructures. It is also
important to point out that although compounds such as 62–64 have “free” sulfhydryl groups (Cys) there
is no evidence that they become farnesylated, and therefore the binding mode and effect on catalytic
function of the target enzyme are unique relative to their peptide substrate counterparts. Recently, a
novel peptide inhibitor series, as exemplified by Cbz-His-Try(O-benzyl)-Ser(O-benzyl)-Trp-D-Ala-NH 2,
has been discovered [76]. These inhibitors do not contain a Cys residue and structure-based design
efforts have successfully led to a series of peptidomimetics (e.g., 65) having only one chiral center.
Interestingly, this novel inhibitor series has been determined to competitively inhibit farnesyl
pyrophosphate binding rather than the binding of peptide substrate to the target enzyme. Another Hissubstituted
peptidomimetic inhibitor of Ras farnesyl transferase has been recently reported [84] as
exemplified by 73, which was designed relative to a peptide substrate-based parent analog (72, Figure
15). Although the 3D structure of Ras farnesyl transferase is not known, biochemical studies suggest
that a divalent metal ion (e.g., Zn 2+) may coordinate with the above inhibitor sulfhydryl or imidazole
groups at their corresponding binding sites on the target enzyme.
Another example of the signal-transduction protein-targeted drug design that illustrates peptide scaffoldbased
approaches is that for Src SH2 domain antagonist discovery. Such compounds show promise as
new therapeutic agents for Src-related carcinogenesis, osteoporosis, and immune diseases [85]. The Src
SH2 domain is a prototype example of a superfamily of intracellular signal-transduction proteins that
possess structurally homologous SH2 domains that specifically recognize cognate phosphoproteins in a
sequence-dependent manner relative to a critical phosphotyrosine (pTyr) residue (i.e., ~pTyr-AA 1-AA 2-
AA 3-AA 4~ Furthermore, recent x-ray crystallographic studies of a several SH2 protein targets (e.g.,
phosphopeptide complexes) is greatly impacting the
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