McDermott Lee, Koes David, Mohammed Shabber, Iyer Prema, Boby Melissa, Balasubramanian Venkatakrishnan, Geedy Mackenzie, Katt William, Cerione Richard
University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15260, USA; University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15269, USA.
University of Pittsburgh, Department of Computational and Systems Biology, Pittsburgh, PA 15260, USA.
Bioorg Med Chem Lett. 2019 Oct 1;29(19):126632. doi: 10.1016/j.bmcl.2019.126632. Epub 2019 Aug 20.
Allosteric inhibitors of glutaminase (GAC), such as BPTES, CB-839 and UPGL00019, have great promise as inhibitors of cancer cell growth, but potent inhibitors with drug-like qualities have been difficult to achieve. Here, a small library of GAC inhibitors based on the UPGL00019 core is described. This set of derivatives was designed to assess if one or both of the phenylacetyl groups flanking the UPGL00019 core can be replaced by smaller simple aliphatic acyl groups without loss in potency. We found that one of the phenylacetyl moieties can be replaced by a set of small aliphatic moieties without loss in potency. We also found that enzymatic potency co-varies with the VDW volume or the maximum projection area of the groups used as replacements of the phenylacetyl moiety and used literature X-ray data to provide an explanation for this finding.
谷氨酰胺酶（GAC）的变构抑制剂，如BPTES、CB - 839和UPGL00019，作为癌细胞生长抑制剂具有很大潜力，但具有类药物性质的强效抑制剂一直难以实现。在此，描述了一个基于UPGL00019核心的GAC抑制剂小型文库。这组衍生物旨在评估UPGL00019核心两侧的一个或两个苯乙酰基是否可以被更小的简单脂肪族酰基取代而不损失效力。我们发现其中一个苯乙酰基部分可以被一组小脂肪族部分取代而不损失效力。我们还发现酶活性与用作苯乙酰基部分替代物的基团的范德华体积或最大投影面积共同变化，并利用文献中的X射线数据对这一发现作出解释。
