-
1.
QSAR-guided pharmacophoric modeling reveals important structural requirements for Polo kinase 1 (Plk1) inhibitors.
Shahin, R, Al-Hashimi, NN, Daoud, NE, Aljamal, S, Shaheen, O
Journal of molecular graphics & modelling. 2021;:108022
Abstract
Targeting Polo-like kinase 1 (Plk1) by molecular inhibitors is being a promising approach for tumor therapy. Nevertheless, insufficient methodical analyses have been done to characterize the interactions inside the Plk1 binding pocket. In this study, an extensive combined ligand and structure-based drug design workflow was conducted to data-mine the structural requirements for Plk1 inhibition. Consequently, the binding modes of 368 previously known Plk1 inhibitors were investigated by pharmacophore generation technique. The resulted pharmacophores were engaged in the context of Genetic function algorithm (GFA) and Multiple linear regression (MLR) analyses to search for a prognostic QSAR model. The most successful QSAR model was with statistical criteria of (r2277 = 0.76, r2adj = 0.76, r2pred = 0.75, Q2 = 0.73). Our QSAR-selected pharmacophores were validated by Receiver Operating Characteristic (ROC) curve analysis. Later on, the best QSAR model and its associated pharmacophoric hypotheses (HypoB-T4-5, HypoI-T2-7, HypoD-T4-3, and HypoC-T3-3) were used to identify new Plk1 inhibitory hits retrieved from the National Cancer Institute (NCI) database. The most potent hits exhibited experimental anti-Plk1 IC50 of 1.49, 3.79. 5.26 and 6.35 μM. Noticeably, our hits, were found to interact with the Plk1 kinase domain through some important amino acid residues namely, Cys67, Lys82, Cys133, Phe183, and Asp194.
-
2.
Ten-eleven translocase: key regulator of the methylation landscape in cancer.
Shekhawat, J, Gauba, K, Gupta, S, Choudhury, B, Purohit, P, Sharma, P, Banerjee, M
Journal of cancer research and clinical oncology. 2021;(7):1869-1879
Abstract
PURPOSE Methylation of 5th residue of cytosine in CpG island forms 5-methylcytosine which is stable, heritable epigenetic mark. Methylation levels are broadly governed by methyltransferases and demethylases. An aberration in the demethylation process contributes to the silencing of gene expression. Ten eleven translocation (TET) dioxygenase (1-3) the de novo demethylase is responsible for conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosisne (5-fC) and 5-carboxycytosine (5-caC) during demethylation process. Mutations and abnormal expression of TET proteins contribute to carcinogenesis. Discovery of TET proteins has offered various pathways for the reversal of methylation levels thus, enhancing our knowledge as to how methylation effects cancer progression. METHODS We searched "PubMed" and "Google scholar" databases and selected studies with the following keywords "TET enzyme", "cancer", "5-hmC", and "DNA demethylation". In this review, we have discussed combinatorial use of vitamin C in inhibiting tumour growth by enhancing the catalytic activity of TET enzymes and consequently, increasing the 5-hmC levels. 5-Hydroxymethylcytosine holds promise as a prognostic biomarker in solid cancers. The contribution of induction and suppression of TET enzymes and 5-hmC carcinogenesis are discussed in haematological and solid cancers. RESULTS We found that TET enzymes play central role in maintaining the methylation balance. Any anomaly in their expression may dip the balance towards cancer progression. Low levels of TET enzymes and 5-hmC correlate with tumour invasion, progression and metastasis. Also, use of vitamin C enhances TET activity. CONCLUSION TET enzymes play vital role in shaping the methylation landscape in body. 5-hmC can be used as prognostic marker in solid cancers.
-
3.
Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs.
Le-Niculescu, H, Roseberry, K, Levey, DF, Rogers, J, Kosary, K, Prabha, S, Jones, T, Judd, S, McCormick, MA, Wessel, AR, et al
Molecular psychiatry. 2020;(5):918-938
-
-
Free full text
-
Abstract
The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.
-
4.
Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction.
Rasafar, N, Barzegar, A, Mehdizadeh Aghdam, E
Scientific reports. 2020;(1):11449
Abstract
MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes' ΔGbinding extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔGbinding to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent.
-
5.
Par-4 regulates autophagic cell death in human cancer cells via upregulating p53 and BNIP3.
Thayyullathil, F, Cheratta, AR, Pallichankandy, S, Subburayan, K, Tariq, S, Rangnekar, VM, Galadari, S
Biochimica et biophysica acta. Molecular cell research. 2020;(7):118692
Abstract
Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that selectively induces apoptosis in cancer cells. Although the mechanism of Par-4-mediated induction of apoptosis has been well studied, the involvement of Par-4 in other mechanisms of cell death such as autophagy is unclear. We investigated the mechanism involved in Par-4-mediated autophagic cell death in human malignant glioma. We demonstrate for the first time that the tumor suppressor lipid, ceramide (Cer), causes Par-4 induction, leading to autophagic cell death in human malignant glioma. Furthermore, we identified the tumor suppressor protein p53 and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) as downstream targets of Par-4 during Cer-mediated autophagic cell death. RNAi-mediated down-regulation of Par-4 blocks Cer-induced p53-BNIP3 activation and autophagic cell death, while upregulation of Par-4 augmented p53-BNIP3 activation and autophagic cell death. Remarkably, in many instances, Par-4 overexpression alone was sufficient to induce cell death which is associated with features of autophagy. Interestingly, similar results were seen when glioma cells were exposed to classical autophagy inducers such as serum starvation, arsenic trioxide, and curcumin. Collectively, the novel Par-4-p53-BNIP3 axis plays a crucial role in autophagy-mediated cell death in human malignant glioma.
-
6.
The Genetics of Pneumothorax.
Boone, PM, Scott, RM, Marciniak, SJ, Henske, EP, Raby, BA
American journal of respiratory and critical care medicine. 2019;(11):1344-1357
-
-
Free full text
-
Abstract
A genetic influence on spontaneous pneumothoraces-those occurring without a traumatic or iatrogenic cause-is supported by several lines of evidence: 1) pneumothorax can cluster in families (i.e., familial spontaneous pneumothorax), 2) mutations in the FLCN gene have been found in both familial and sporadic cases, and 3) pneumothorax is a known complication of several genetic syndromes. Herein, we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1 antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis, Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others. At times, pneumothorax is their herald manifestation. These syndromes have serious potential extrapulmonary complications (e.g., malignant renal tumors in Birt-Hogg-Dubé syndrome), and surveillance and/or treatment is available for most disorders; thus, establishing a diagnosis is critical. To facilitate this, we provide an algorithm to guide the clinician in discerning which cases of spontaneous pneumothorax may have a genetic or familial contribution, which cases warrant genetic testing, and which cases should prompt an evaluation by a geneticist.
-
7.
Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.
Al-Zebeeby, A, Vogler, M, Milani, M, Richards, C, Alotibi, A, Greaves, G, Dyer, MJS, Cohen, GM, Varadarajan, S
Haematologica. 2019;(5):1016-1025
Abstract
BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.
-
8.
The critical roles of TBC proteins in human diseases.
Shi, MT, Zhang, Y, Zhou, GQ
Yi chuan = Hereditas. 2018;(1):12-21
Abstract
The Tre-2/Bub2/Cdc16 (TBC) domain is a conserved protein motif consisting of approximately 200 amino acids, and is present in many eukaryotic proteins. TBC domain-containing proteins (TBC proteins) function as GTPase activating proteins (GAPs) for the small GTPase Rab, which can promote the hydrolysis of Rab-GTP to Rab-GDP in regulation of specific intracellular trafficking pathways. Several TBC proteins play important roles in cellular functions in mammals, and defects of which are closely associated with numerous disease processes. In this review, we summarize the structures and functions of the mammalian TBC proteins and recent advances in understanding their critical roles in the development of human diseases. This review serves as a reference for further investigations on the functions of TBC proteins in disease pathogeneses.
-
9.
Microphthalmia is not a mandatory finding in X-linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu.
Kraus, C, Uebe, S, Thiel, CT, Ekici, AB, Reis, A, Zweier, C
American journal of medical genetics. Part A. 2018;(12):2872-2876
Abstract
Mutations in BCOR cause X-linked dominant and X-linked recessive forms of syndromic microphthalmia. By exome sequencing, we identified the recurrent BCOR mutation p.Pro85Leu in two brothers and their unaffected mother. While the older brother's phenotype completely fits the described phenotypic spectrum of X-linked recessive BCOR-associated Lenz microphthalmia syndrome, the younger brother showed developmental delay, microcephaly, and skeletal anomalies, but not the key feature of microphthalmia. In contrast to the previously published families, our findings demonstrate a large variability of BCOR-associated, syndromic phenotypes, indicating incomplete penetrance of p.Pro85Leu with regards to microphthalmia in males.
-
10.
FLCN: The causative gene for Birt-Hogg-Dubé syndrome.
Schmidt, LS, Linehan, WM
Gene. 2018;:28-42
-
-
Free full text
-
Abstract
Germline mutations in the novel tumor suppressor gene FLCN are responsible for the autosomal dominant inherited disorder Birt-Hogg-Dubé (BHD) syndrome that predisposes to fibrofolliculomas, lung cysts and spontaneous pneumothorax, and an increased risk for developing kidney tumors. Although the encoded protein, folliculin (FLCN), has no sequence homology to known functional domains, x-ray crystallographic studies have shown that the C-terminus of FLCN has structural similarity to DENN (differentially expressed in normal cells and neoplasia) domain proteins that act as guanine nucleotide exchange factors (GEFs) for small Rab GTPases. FLCN forms a complex with folliculin interacting proteins 1 and 2 (FNIP1, FNIP2) and with 5' AMP-activated protein kinase (AMPK). This review summarizes FLCN functional studies which support a role for FLCN in diverse metabolic pathways and cellular processes that include modulation of the mTOR pathway, regulation of PGC1α and mitochondrial biogenesis, cell-cell adhesion and RhoA signaling, control of TFE3/TFEB transcriptional activity, amino acid-dependent activation of mTORC1 on lysosomes through Rag GTPases, and regulation of autophagy. Ongoing research efforts are focused on clarifying the primary FLCN-associated pathway(s) that drives the development of fibrofolliculomas, lung cysts and kidney tumors in BHD patients carrying germline FLCN mutations.