Zhao Bin, Sensintaffar John, Bian Zhiguo, Belmar Johannes, Lee Taekyu, Olejniczak Edward T, Fesik Stephen W
Department of Biochemistry, Vanderbilt University, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, USA.
Department of Biochemistry, Vanderbilt University, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, USA.
Bioorg Med Chem. 2017 Jun 15;25(12):3087-3092. doi: 10.1016/j.bmc.2017.03.060. Epub 2017 Mar 29.
Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.
髓细胞白血病-1（Mcl-1）编码基因的扩增是人类癌症中最常见的基因畸变之一，与肿瘤分级高和生存率低相关。最近，我们报道了高亲和力Mcl-1抑制剂的发现，这些抑制剂引发基于机制的细胞活性。这些抑制剂具有亲脂性且含有酸性官能团，这是血浆中与白蛋白结合的化合物常见的化学特征。事实上，这些Mcl-1抑制剂在血清存在下体外细胞活性降低。在此我们描述了一种先导Mcl-1抑制剂与人类血清白蛋白（HSA）结合时的结构。与许多结合到药物位点1或2的酸性亲脂性化合物不同，我们发现这种Mcl-1抑制剂主要结合到药物位点3。HSA的位点3可能能够容纳更大、更刚性的化合物，这些化合物无法适配较小的药物位点1或2。与该第三位点结合的分子的结构研究可能有助于深入了解一些较高分子量化合物如何与白蛋白结合，并可用于辅助设计白蛋白结合减少的化合物。
