Patel D V, Young M G, Robinson S P, Hunihan L, Dean B J, Gordon E M
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 1996 Oct 11;39(21):4197-210. doi: 10.1021/jm960190h.
The rational design, synthesis, and activity of novel, hydroxamic acid-based, collective bisubstrate analog inhibitors of farnesyl protein transferase (FPT) is described. This class of compounds differ structurally from the conventional FPT inhibitors by being non-sulfhydryl and by being bisubstrate based rather than peptide or FPP derived inhibitors. Whereas replacement of the sulfhydryl group of tetrapeptide CVLS (I50 = 1 microM) by an N-methylhydroxamic acid had a deleterious effect (10, I50 > 360 microM), moderate inhibition was realized with 16 (I50 = 42.5 microM), a bisubstrate analog involving anchorage of farnesyl and tripeptide groups by a hydroxamic acid-embedded linker. Starting from 16, a 1 order of magnitude improvement in in vitro potency was obtained by optimization of the linker (20, I50 = 4.35 microM). An additional 13-fold enhancement was achieved by substituting the tripeptide moiety VLS in 20 by VVM (23, I50 = 0.33 microM). The dependence of these inhibitors on their peptide and farnesyl subunits is suggestive of their bisubstrate nature. Compound 23 (I50 = 0.33 microM) is 2 orders of magnitude better in activity compared to the initial lead 16 [I50 = 42.5 microM) and is effective in blocking prenylation of protein in whole cells including p21ras.
本文描述了新型基于异羟肟酸的法尼基蛋白转移酶（FPT）双底物类似物抑制剂的合理设计、合成及活性。这类化合物在结构上与传统的FPT抑制剂不同，它们不含巯基，且是基于双底物的，而非肽类或法尼基焦磷酸（FPP）衍生的抑制剂。用N - 甲基异羟肟酸取代四肽CVLS（I50 = 1 microM）的巯基会产生有害影响（10，I50 > 360 microM），而双底物类似物16（I50 = 42.5 microM）则实现了适度抑制，该双底物类似物通过嵌入异羟肟酸的连接子将法尼基和三肽基团连接起来。从16开始，通过优化连接子（20，I50 = 4.35 microM），体外效力提高了1个数量级。用VVM取代20中的三肽部分VLS（23，I50 = 0.33 microM），又实现了13倍的增强。这些抑制剂对其肽和法尼基亚基的依赖性表明它们具有双底物性质。化合物23（I50 = 0.33 microM）的活性比初始先导化合物16 [I50 = 42.5 microM] 高2个数量级，并且能有效阻断包括p21ras在内的全细胞中蛋白质异戊二烯化。
