Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chemistry design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compounds that have progressed into clinical development or that have revealed new structural motifs in this highly competitive area of research

Ipratropium is ‘luminally recycled’ by an inter-play between apical uptake and efflux transporters in Calu-3 bronchial epithelial cell layers

The mechanism by which quaternized anticholinergic bronchodilators permeate the airway epithelium remains controversial to date. In order to elucidate the role of drug transporters, ipratropium bidirectional transport as well as accumulation and release studies were performed in layers of the broncho-epithelial cell line Calu-3 grown at an air-liquid interface, in presence or absence of a range of transporter inhibitors. Unexpectedly, a higher transepithelial permeability was observed in the secretory direction, with an apparent efflux ratio >4. Concentration-dependent and inhibitor studies demonstrated the drug intracellular uptake was carrier-mediated. Interestingly, monitoring drug release post cell loading revealed the presence of an efficient efflux system on the apical side of the cell layers. Acting in concert, apical transporters seem to promote the ‘luminal recycling’ of the drug and hence, limit its transcellular transport. The data are in agreement with an apical Organic Cation Transporter (OCT) being involved in this process but also suggest the participation of unknown uptake and efflux transporters sensitive to probenecid. This study suggests the absorption of ipratropium across the pulmonary barrier is primarily governed by paracellular passive diffusion but transporters might play a significant role in controlling the drug local concentrations in the lungs

The Impact of PBL as a STEM School Reform Model

Project/problem-based learning (PBL) can provide an effective model for school reform when implemented with fidelity. In the report, Rising Above the Gathering Storm, it was recommended that if the U.S. is to remain competitive in the 21st-century economy, there must be a serious effort to “enlarge the pipeline of students who are prepared to enter college and graduate with a degree in STEM” (National Academy of Sciences, National Academy of Engineering, & Institute of Medicine, 2007, p. 6). The report included the recommendation that states develop statewide specialty STEM high schools (National Academy of Sciences, National Academy of Engineering, & Institute of Medicine, 2007, p. 6). In 2010, the Texas Science, Technology, Engineering, and Mathematics Academy (T-STEM) initiative was implemented to develop specialty STEM schools similar to those described in Rising Above the Gathering Storm. The primary instructional strategy of T-STEM academies is problem- and project-based learning. In the STEM context, PBL is well suited as a primary pedagogy for STEM learning. This paper examines the following questions: What outcomes occur when PBL is implemented in a low performing school district? What is the role of PBL in school improvement? What are the challenges to implementing PBL with high fidelity

The Texas Earth and Space Science (TXESS) Revolution: A Model for the Delivery of Earth Science Professional Development to Minority-Serving Teachers

At the time of publication K.K. Ellins, E. Snow, H.C. Olson, M. Willis, and J. Olson were at the University of Texas Austin, E. Stocks and M.R. Odell were at the University of Texas at Tyler.The Texas Earth and Space Science (TXESS) Revolution was a 5-y teacher professional development project that aimed to increase teachers' content knowledge in Earth science and preparing them to teach a 12th-grade capstone Earth and Space Science course, which is new to the Texas curriculum. The National Science Foundation–supported project was designed around six principles that proved to be critical to in its success: (1) model best practices in workshop presentations, (2) use authentic Earth science data and cybertechnology to teach up-to-date content, (3) provide ongoing training to cohorts of learners over a 2-y period, (4) involve geoscience consortia and programs that can provide proven content for classrooms, (5) use ongoing evaluations to guide future workshops, and (6) provide opportunities for leadership development through participation in research and curriculum development projects. The project served 177 science teachers by supporting them with the pedagogical, technological, and scientific tools to teach modern geoscience. TXESS Revolution teachers directly impacted more than 29,000 students, of which about 69% are nonwhite, by exposing students in Texas to the geosciences and planting the seeds for them to pursue geoscience as a field of study. Using a train-the-trainer approach, TXESS Revolution teachers shared their professional development with other Texas teachers, strengthening Earth science education at all K–12 levels throughout the state, an impact that extends beyond preparation in Earth and space science.Petroleum and Geosystems Engineerin

Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation

Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR

© 2020 The Authors Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation

Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925

The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y2R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y2R antagonists leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1). One of these conjugates 98 displayed micromolar affinity for the hP2Y2R (pKd = 6.32 ± 0.10; n=17) using a bioluminescence energy transfer (BRET) assay. Confocal microscopy with this ligand revealed displaceable membrane labeling of astrocytoma cells expressing un-tagged hP2Y2R. These properties, make 98 one of the first tools for studying hP2Y2R distribution and organization

Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery

Drug-like antagonists of P2Y receptors — from lead identification to drug development

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation