Hymel David, Burke Terrence R
Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Frederick, MD, 21702, USA.
ChemMedChem. 2017 Feb 3;12(3):202-206. doi: 10.1002/cmdc.201600574. Epub 2017 Jan 9.
(2S,3R)-2-Amino-3-methyl-4-phosphonobutanoic acid (Pmab) is a phosphatase-stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagent. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R center. When incorporated into our peptidomimetic scaffold, these new Pmab analogues exhibit Plk1 PBD-binding affinities that are several-fold higher than Pmab, yet retain good selectivity for Plk1 relative to the PBDs of Plk2 and Plk3. These findings will significantly impact the future development of PBD-binding inhibitors, as well as ligands directed against a broad spectrum of pThr-dependent processes.
(2S,3R)-2-氨基-3-甲基-4-膦酰基丁酸（Pmab）是磷酸苏氨酸（pThr）的一种磷酸酶稳定类似物，已在多种生物学背景中使用。这些应用包括与polo样激酶1（Plk1）的polo盒结构域（PBD）结合的拟肽配体，其亲和力接近相应含pThr肽段的亲和力。然而，Pmab并未得到广泛应用，因为没有合适保护试剂的直接、高产率制备方法。我们现已实现了受保护Pmab以及在3R中心带有不同取代基的变体的高效合成。当将这些新的Pmab类似物纳入我们的拟肽支架时，它们表现出比Pmab高几倍的Plk1 PBD结合亲和力，同时相对于Plk2和Plk3的PBDs对Plk1仍保持良好的选择性。这些发现将对PBD结合抑制剂以及针对广泛的pThr依赖性过程的配体的未来发展产生重大影响。
