Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides.

Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cyclic AMP (cAMP)-response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a negative regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biological and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.

Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors.

Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 µM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents.

Gyrase ATPase domain as an antitubercular drug discovery platform: structure-based design and lead optimization of nitrothiazolyl carboxamide analogues.

In this study, we explored the pharmaceutically underexploited mycobacterial gyrase ATPase (GyrB) domain as a template for a structure-based virtual screening of our in-house (BITS Pilani) compound collection to discover new inhibitors targeting Mycobacterium tuberculosis (M.tb.) The hit identified was further customized by using a combination of molecular docking and medicinal chemistry strategies to obtain an optimized analogue displaying considerable in vitro enzyme efficacy and bactericidal properties against the M.tb. H37 Rv strain. The binding affinity of the ligand toward the GyrB domain was reascertained by differential scanning fluorimetry experiments. Further evaluation of the hERG toxicity (a major limitation among the previously reported N-linked aminopiperidine analogues) indicated these molecules to be completely devoid of cardiotoxicity, a significant achievement within this class.