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Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism., (© 2024. The Author(s).)

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC., (© 2023. The Author(s).)

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We evaluated the cost-effectiveness of a genotype-guided strategy among patients with acute coronary syndromes using a decision-tree model based on the Singapore healthcare payer's perspective over a 1-year time horizon. Three dual antiplatelet strategies were considered: universal clopidogrel, genotype-guided, and universal ticagrelor. The prevalence of loss-of-function alleles was assumed to be 61.7% and model inputs were identified from the literature. Our primary outcome of interest was incremental cost-effectiveness ratio (ICER) compared to universal clopidogrel. Both genotype-guided (72,158 SGD/QALY) and universal ticagrelor (82,269 SGD/QALY) were considered cost-effective based on a willingness-to-pay (WTP) threshold of SGD 88,991. In our secondary analysis, the ICER for universal ticagrelor was 114,998 SGD/QALY when genotype-guided was taken as a reference. Probabilistic sensitivity analysis revealed that genotype-guided was the most cost-effective strategy when the WTP threshold was between SGD 70,000 to 100,000. Until more data are available, our study suggests that funding for a once-off CYP2C19 testing merits a consideration over 1 year of universal ticagrelor.

We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct permeability properties, in addition to active drug efflux, making this cell envelope impermeable to most compounds. Second, chemical libraries currently used in drug discovery contain few compounds that can penetrate Gram-negative bacteria. As a result of these challenges, intensive screening campaigns have led to few successes, highlighting the need for new approaches to identify regions of chemical space that are specifically relevant to antibacterial drug discovery. Herein we provide an overview of emerging insights into this problem and outline a general approach to addressing it using prospective analysis of chemical libraries for the ability of compounds to accumulate in Gram-negative bacteria. The overall goal is to develop robust cheminformatic tools to predict Gram-negative permeation and efflux, which can then be used to guide medicinal chemistry campaigns and the design of antibacterial discovery libraries.

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

Sample heterogeneity often masks DNA methylation signatures in subpopulations of cells. Here, we present a method to genotype single cells while simultaneously interrogating gene expression and DNA methylation at multiple loci. We used this targeted multimodal approach, implemented on an automated, high-throughput microfluidic platform, to assess primary lung adenocarcinomas and human fibroblasts undergoing reprogramming by profiling epigenetic variation among cell types identified through genotyping and transcriptional analysis.

The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.

Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.

Several drugs targeting poly(ADP-ribose) polymerase (PARP) enzymes are under development. Responses have been observed in patients with germline mutations in BRCA1 and BRCA2, with further data supporting antitumour activity of PARP inhibitors in sporadic ovarian cancer. Strategies to identify other predictive biomarkers remain under investigation. Iniparib was purported to be a PARP inhibitor that showed promising results in randomized phase II trials in patients with triple-negative breast cancer. Negative results from a phase III study in this disease setting, however, tempered enthusiasm for this agent. Recently, data from in vitro experiments suggest that iniparib is not only structurally distinct from other described PARP inhibitors, but is also a poor inhibitor of PARP activity. In this context, the negative iniparib phase III data might have erroneously promulgated the notion that PARP inhibition is not an effective therapeutic strategy. Here, we scrutinize the development of iniparib from preclinical studies to registration trials, and identify and discuss the pitfalls in the development of anticancer drugs to prevent future late-stage trial failures.

Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer.

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.

Weekly paclitaxel is a highly active and well tolerated regimen that is increasingly being adopted for the treatment of relapsed ovarian cancer. This regimen is usually administered at 80-90 mg/m(2)/week, and the use of a 1 h infusion helps minimize myelosuppression. When compared with the 3-weekly schedule, weekly paclitaxel is better tolerated, with a reduced frequency of grade 3-4 toxic effects. Single-agent weekly paclitaxel for relapsed ovarian cancer yields response rates in the range of 20-62%; however, response duration can be short. Responses to weekly paclitaxel have been observed in patients whose tumors are resistant to 3-weekly paclitaxel. The level of activity of weekly paclitaxel for relapsed disease has led to its detailed evaluation in the first-line setting, and interest has been enhanced by the results of a Japanese Gynecological Oncology Group study that demonstrated a survival advantage for weekly paclitaxel compared with 3-weekly paclitaxel in combination with carboplatin as initial treatment. The enhanced efficacy of weekly paclitaxel may be due to greater drug exposure, a direct antiangiogenic effect, or both. Current research topics include the combination of weekly paclitaxel with molecular-targeted agents and the use of molecular profiling to better select patients for treatment.

Diversity-oriented synthesis (DOS) is an emerging field involving the synthesis of combinatorial libraries of diverse small molecules for biological screening. Rather than being directed toward a single biological target, DOS libraries can be used to identify new ligands for a variety of targets. Several different strategies for library design have been developed to target the biologically relevant regions of chemical structure space. DOS has provided powerful probes to investigate biological mechanisms and also served as a new driving force for advancing synthetic organic chemistry.

Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health and potential use as agents of bioterrorism. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity. Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host, where the free iron concentration is well below that required for bacterial growth and virulence. Thus, siderophore biosynthesis is an attractive target in the development of new antibiotics to treat tuberculosis and plague. In particular, such drugs, alone or as part of combination therapies, could provide a valuable new line of defense against intractable multiple-drug-resistant infections. Here, we report the design, synthesis and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for siderophore biosynthesis in M. tuberculosis and Y. pestis. This new antibiotic inhibits siderophore biosynthesis and growth of M. tuberculosis and Y. pestis under iron-limiting conditions.