Koide K, Bunnage M E, Gomez Paloma L, Kanter J R, Taylor S S, Brunton L L, Nicolaou K C
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093, USA.
Chem Biol. 1995 Sep;2(9):601-8. doi: 10.1016/1074-5521(95)90124-8.
The protein kinase C (PKC) family of serine/threonine-specific protein kinases is involved in many cellular processes, and the unregulated activation of PKC has been implicated in carcinogenesis. PKC inhibitors thus have significant potential as chemotherapeutic agents. Recently, the fungal metabolite balanol was shown to be an exceptionally potent inhibitor of PKC. We previously developed a practical and efficient total synthesis of balanol. We set out to use this synthetic molecule, and several synthetic analogs, to probe the mechanism of PKC inhibition and to determine the effect of balanol on the activity of other protein kinases.
As well as inhibiting PKC, balanol is a potent inhibitor of cyclic AMP-dependent protein kinase (PKA), another protein serine/threonine kinase. Balanol does not, however, inhibit the Src or epidermal growth factor receptor protein tyrosine kinases. The inhibition of both PKC and PKA by balanol can be overcome by high concentrations of ATP, and molecular modeling studies suggest that balanol may function as an ATP structural analog. Although balanol discriminates rather poorly between PKC and PKA, only minor modifications to its molecular structure are required to furnish compounds that are highly specific inhibitors of PKA.
A number of balanol analogs have been designed and synthesized that, unlike balanol itself, exhibit dramatic selectivity between PKA and PKC. Thus, despite the substantial homology between the catalytic domains of PKA and PKC, there is enough difference to allow for the development of potent and selective inhibitors acting in this region. These inhibitors should be useful tools for analyzing signal transduction pathways and may also aid in the development of drugs with significant therapeutic potential.
丝氨酸/苏氨酸特异性蛋白激酶的蛋白激酶C（PKC）家族参与许多细胞过程，PKC的失控激活与致癌作用有关。因此，PKC抑制剂作为化疗药物具有巨大潜力。最近，真菌代谢产物巴拉诺醇被证明是一种异常有效的PKC抑制剂。我们之前开发了一种实用且高效的巴拉诺醇全合成方法。我们着手使用这种合成分子以及几种合成类似物来探究PKC抑制机制，并确定巴拉诺醇对其他蛋白激酶活性的影响。
除了抑制PKC外，巴拉诺醇还是环磷酸腺苷依赖性蛋白激酶（PKA）的一种有效抑制剂，PKA是另一种蛋白丝氨酸/苏氨酸激酶。然而，巴拉诺醇并不抑制Src或表皮生长因子受体蛋白酪氨酸激酶。高浓度的ATP可以克服巴拉诺醇对PKC和PKA的抑制作用，分子建模研究表明巴拉诺醇可能作为ATP结构类似物发挥作用。尽管巴拉诺醇对PKC和PKA的区分能力较差，但只需对其分子结构进行微小修饰就能得到对PKA具有高度特异性抑制作用的化合物。
已经设计并合成了许多巴拉诺醇类似物，与巴拉诺醇本身不同，它们在PKA和PKC之间表现出显著的选择性。因此，尽管PKA和PKC的催化结构域之间存在大量同源性，但仍有足够差异允许开发作用于该区域的强效和选择性抑制剂。这些抑制剂应该是分析信号转导途径的有用工具，也可能有助于开发具有巨大治疗潜力的药物。
