Lee McDermott's research while affiliated with University of Pittsburgh and other places

Publications (22)

Article
Full-text available
Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e. the “Warburg effect”), and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this ‘glutamine addiction’ of cancer cells by catalyzing the hydrolysis of gluta...
Preprint
Full-text available
Many cancer cells become dependent on glutamine metabolism to compensate for glycolysis being uncoupled from the TCA cycle. The mitochondrial enzyme Glutaminase C (GAC) satisfies this "glutamine addiction" by catalyzing the first step in glutamine metabolism, making it an attractive drug target. Despite one of the allosteric inhibitors (CB-839) bei...
Article
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 on...
Article
The purpose of this review is to highlight the pharmacological barrier to drug development for traumatic brain injury (TBI) and to discuss best practice strategies to overcome such barriers. Specifically, this article will review the pharmacological considerations of moving from the disease target "hit" to the "lead" compound with drug-like and cen...
Article
Full-text available
Altered glycolytic flux in cancer cells (the Warburg effect) causes their proliferation to rely upon elevated glutamine metabolism (glutamine addiction). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small mole...
Article
Full-text available
Profilin1 (Pfn1) is an important regulator of the actin cytoskeleton and plays a vital role in many actin-based cellular processes. Therefore, identification of a small-molecule intervention strategy targeted against the Pfn1:actin interaction could have broad utility in cytoskeletal research and further our understanding of the role of Pfn1 in act...
Article
Full-text available
Quantitative Systems Pharmacology (QSP) is a drug discovery approach that integrates computational and experimental methods in an iterative way to gain a comprehensive, unbiased understanding of disease processes to inform effective therapeutic strategies. We report the implementation of QSP to Huntington's Disease, with the application of a chemog...
Article
Full-text available
A novel set of GAC (Kidney Glutaminase Isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when c...
Article
Full-text available
Serine hydroxymethyltransferase (SHMT) is a central enzyme in the metabolic reprogramming of cancer cells, providing activated one-carbon units in the serine-glycine one-carbon metabolism. Previous studies demonstrated that the cytoplasmic isoform of SHMT (SHMT1) plays a relevant role in lung cancer. SHMT1 is overexpressed in lung cancer patients a...
Article
Full-text available
No therapies have been shown to accelerate recovery or prevent fibrosis after acute kidney injury (AKI). In part this is because most therapeutic candidates have to be given at the time of injury and the diagnosis of AKI is usually made too late for drugs to be efficacious. Strategies to enhance post-AKI repair represent an attractive approach to a...
Article
Metabolic reprogramming of tumor cells toward serine catabolism is now recognized as a hallmark of cancer. Serine hydroxymethyltransferase (SHMT), the enzyme providing one-carbon units by converting serine and tetrahydrofolate (H4 PteGlu) to glycine and 5,10-CH2 -H4 PteGlu, therefore represents a target of interest in developing new chemotherapeuti...
Article
Platinum based anticancer agents, including cisplatin, are among the most effective and widely used anticancer drugs. However, inherent and acquired resistance to these drugs in tumors lead to treatment failure. We found a class of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that overcome both the inhe...
Article
Full-text available
Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplati...
Article
Full-text available
PTBAs are a new class of HDAC inhibitors that accelerate recovery and reduce post-injury fibrosis after ischemia-reperfusion-induced acute kidney injury. However, unlike the more common scenario in which patients present with protracted and less clearly defined onset of renal injury, this model of acute kidney injury gives rise to a clearly defined...
Article
Platinum based anticancer agents including cisplatin are among the most effective and widely used anticancer drugs. However, the inherent and acquired resistance to these drugs in tumors present significant challenges in cancer treatment and directly lead to treatment failure. We have identified a number of thioquinazolinone derivatives, including...
Article
Full-text available
Reactivation of genes normally expressed during organogenesis is a characteristic of kidney regeneration. Enhancing this reactivation could potentially be a therapeutic target to augment kidney regeneration. The inductive events that drive kidney organogenesis in zebrafish are similar to the initial steps in mammalian kidney organogenesis. Therefor...
Article
Full-text available
At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from...

Citations

... We begin our study by choosing a library of 974 molecules which are potential inhibitors of the Glutaminase C protein [44,45] (the GAC library -the list of molecules in the dataset is provided in the Supplementary material). We generate chemical similarity networks from this library using two different sets of molecular descriptors, namely Transferable Atom Equivalent Reconstruction (RECON) [46][47][48] and Molecular Operating Environment (MOE) [49,50] descriptors (provided in the Supplementary material). ...
... However, the terminal rings of the most potent UPGL series molecules also have these characteristics, suggesting that they are also important for binding to GAC. This supports our earlier work suggesting that inhibitory potency might be influenced by the combined Van der Waals volume of the terminal groups of these inhibitors (31) and is consistent with SAR data showing that for the BPTES/CB-839 class of molecules, the most potent compounds tend to either have aromatic rings (e.g. benzene or pyridine rings) or electron-donating pseudo-aromatic groups such as cyclopropane as terminal groups (3,6,32,33). ...
... These failures have resulted due to a variety of problems during testing for the efficacy of treatments. Clinical trials for testing the efficacy of the pharmacological intervention of progesterone, the glutamate antagonist, CP 101-606, and the antioxidant, Tirilazad, each resulted in negative outcomes during Phase III trials [11][12][13][14]. Researchers postulate that these failures were the result of suboptimal dosing during Phase II trials suggesting inadequate delivery into the brain and poor target engagement. ...
... ATP-driven efflux transporters [17][18][19]. To overcome these issues, a great effort has been made to find new inhibitors targeting other enzymes, such as SHMT [20][21][22][23][24][25], although with little results to date. ...
... Interestingly, both variants of the GLS enzyme (KGA and GAC) were detected in ACHN cells by a dual-specificity antibody, while 786-O and HK-2 cell lines expressed only the GAC isoform. KGA is considered the full-length GLS, whereas GAC is a C-terminal truncated splice variant [39]. Both the KGA and GAC isoforms are implicated in cancer; however, the GAC/KGA ratio has been described as higher in most tumor types. ...
... Virtual screening is one of the promising computer-aided techniques in identifying new leads for drug development (Shoichet, 2004;Ravindranath et al., 2015;Fradera and Babaoglu, 2017;Hernández-González et al., 2021;Rajguru et al., 2022). Structure-based virtual screening (SBVS) or target-based virtual screening (TBVS) is commonly used for the identification of potential compounds preferentially binding to a drug target (Rosenthal, 2003;Hernández González et al., 2017;Gau et al., 2018;Maia et al., 2020;Rana et al., 2020;Dash et al., 2021). SBVS involves computational methods, including molecular docking and dynamic simulations of receptor-ligand and the complexes (Desai et al., 2004;Rajguru et al., 2021). ...
... The complexity in the molecular pathogenesis of HD that ultimately leads to the progression of the disease makes it an ideal candidate for investigation using QSP approaches. A model to identify mechanisms of disease and neuronal protection from toxicity due to mutant huntingtin was developed from an experimental striatal neuronal cell model of HD treated with small molecule probes and their combinations that exert protective effects 200 . A computational systems level analysis of the perturbed pathways predicted optimal pathways and networks based on phenotypic assays of neuroprotection 201,202 . ...
... Taking into account the significant role of the pyridinyloxy substitutes in the structure of the pharmaceutically active compounds [31][32][33][34][35][36], it was required to insert these substitutes into the composition of new functional derivatives of (benzo)imidazo[2,1-b] [1,3]thiazines. According to our approach to the construction of such systems, 3-hydroxy(benzo)imidazo[2,1b] [1,3]thiazines 2a-c were used as the key substrates. ...
... [8]. SHMT1 isoform (cytoplasmic) overexpression has been in lung cancer, and its lesser activity in lung cancer cell lines was followed by cell arrest and apoptosis [9]. The present review focuses on the three enzymes that can be targeted against many diseases and in this regard hybrid drug designing can play a significant role in combating the targets together. ...
... Additionally, the use of DNA methylation inhibitors (such as 5 -azacytidine and 5-aza-2 -deoxycytidine) or DNA demethylation activators (such as hydralazine) can effectively alleviate renal interstitial fibrosis after ischemia-reperfusion injury [110]. Additionally, there are some reports indicating that the use of HDAC inhibitors, such as TSA, PTBA and their analogues (UPHD25 and 186), can alleviate post-AKI renal injury in mice, accelerate the recovery of renal function and prevent the transition from AKI to CKD [112,119,120]. However, although the targeted epigenetic change interventions are of great significance to prevent the transition from AKI to CKD, there are some issues worth exploring. ...