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Discovery, Structure-Activity Relationship And In Vitro Anticancer Activity Of Small-Molecule Inhibitors Of The Protein-Protein Interactions Between Af9/Enl And Af4 Or Dot1l, Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku, Yongcheng Song

Faculty, Staff and Students Publications

Simple Summary

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for ~75% infant and 5–10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein–protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein–protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein–protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC₅₀ values as …

A Computational Study On The Impact Of Anchoring Groups On The Optical And Electronic Properties Of Triphenylamine-Based Dyes For Dye-Sensitized Solar Cell Applications, Geradius Deogratias, Grace Kinunda

Tanzania Journal of Science

Anchoring groups are crucial for enhancing the performance of dye-sensitized solar cells (DSSCs). For instance, cyanoacrylic acid serves as the primary anchoring group in DSSC due to its crucial elements required for effective electron transport. However, it suffers from degradation. To address this limitation, this study proposes alternative cyano-based anchoring groups for sensitizers. Density functional theory (DFT) and time-dependent DFT were used to investigate the optical and electronic properties of the dyes. The studied dyes (excluding the dye containing OH group) displayed three absorption bands within the visible and NIR regions. Low-energy peaks ranged from 498 to 576 nm, corresponding …

Structure-Activity Relationship And Antitumor Activity Of 1,4-Pyrazine-Containing Inhibitors Of Histone Acetyltransferases P300/Cbp, Shenyou Nie, Fangrui Wu, Jingyu Wu, Xin Li, Chao Zhou, Yuan Yao, Yongcheng Song

Faculty, Staff and Students Publications

Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on …

Structure, Function And Inhibition Of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 And Its Fusion Oncoproteins, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains …

Synthesis, Structure-Activity Relationships, And Antiviral Activity Of Allosteric Inhibitors Of Flavivirus Ns2b-Ns3 Protease, Shenyou Nie, Yuan Yao, Fangrui Wu, Xiaowei Wu, Jidong Zhao, Yuanda Hua, Jingyu Wu, Tong Huo, Yi-Lun Lin, Alexander R Kneubehl, Megan B Vogt, Josephine Ferreon, Rebecca Rico-Hesse, Yongcheng Song

Faculty, Staff and Students Publications

Flaviviruses, including Zika, dengue and West Nile virus, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screen followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile virus and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus …

Small-Molecule Inhibitor Of Af9/Enl-Dot1l/Af4/Aff4 Interactions Suppresses Malignant Gene Expression And Tumor Grow, Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song

Faculty, Staff and Students Publications

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological …

Despite Similar Perceptions And Attitudes, Postbaccalaureate Students Outperform In Introductory Biology And Chemistry Courses, Erin E. Shortlidge, Liz Rain-Griffith, Chloe Shelby, Gwen Shusterman, Jack Barbera

Biology Faculty Publications and Presentations

Embedding active learning is a common mechanism for meeting science, technology, engineering, and mathematics (STEM) education reform goals. Researchers have identified student benefits from such strategies, yet these benefits may not be universal for all students. We sought to identify how students at a nontraditional university perceive introductory biology and chemistry courses, and whether perceptions relate to course type, performance, or student status. We surveyed students (n = 601) using open-ended prompts regarding their perceptions of factors that impact their learning and interest, and about specific learning strategies. Generally, students did not differ in what influenced their learning or …

Deconvoluting The Effects Of Surface Chemistry And Nanoscale Topography: Pseudomonas Aeruginosa Biofilm Nucleation On Si-Based Substrates, Jing Zhang, Jingling Huang, Carmen Say, Robert L. Dorit, Kate Queeney

Chemistry: Faculty Publications

Hypothesis

The nucleation of biofilms is known to be affected by both the chemistry and topography of the underlying substrate, particularly when topography includes nanoscale (nm) features. However, determining the role of topography vs. chemistry is complicated by concomitant variation in both as a result of typical surface modification techniques. Analyzing the behavior of biofilm-forming bacteria exposed to surfaces with systematic, independent variation of both topography and surface chemistry should allow differentiation of the two effects.

Experiments

Silicon surfaces with reproducible nanotopography were created by anisotropic etching in deoxygenated water. Surface chemistry was varied independently to create hydrophilic (OH- terminated) …

Biological Activities Of Phenolic Compounds Extracted From Some Plant Species From East Kalimantan Province, Indonesia, Franxisca Mariani

Chulalongkorn University Theses and Dissertations (Chula ETD)

Ten medicinal plants used in this study are based on the experience of Dayak tribes. The scientific information about these plants are still limited, therefore, the objective of the present study was to analyze their phenolic content and biological activities. A selected species was subjected to successive extraction and compound isolation. The total phenolic content and total antioxidant capacity were analyzed by using Folin-Ciocalteu reagent and the phosphomolybdenum method, respectively. DPPH and ABTS assays were used for analyzing antioxidant activities. The antibacterial activity was performed against six bacterial strains by agar well diffusion and microdilution methods. The anti-tyrosinase activity used …

Connecting Chemistry To Community With Deliberative Democracy, Regis Komperda, Jack Barbera, Erin Shortlidge, Gwen Shusterman, Stem Education And Equity Institute, Portland State University

Biology Faculty Publications and Presentations

Science education communities have called for rethinking curricula to improve student understanding of the nature of science and the role of science in addressing controversial modern issues such as climate change, energy policy, and pollution levels. One approach to meeting this call is integrating these topics into class activities that require students to use discussion and scientific approaches to solve problems and deliberate potential policy solutions. Deliberative democracy (DD) is one such active learning approach in which students work in peer groups to reach a consensus on a scientific topic relevant to both real-world issues and course content. During DD …

Fluorescent Cell Imaging Studies Of Antitumor Natural Macrocycle Ipomoeassin F, Margaret Grace Oliver

Biological Sciences Undergraduate Honors Theses

Ipomoeassin F is one member of a family of macromolecules isolated from the leaves of the morning glory flower, ipomoea squamosa, which has been used as a homeopathic cancer remedy for centuries (Zhu, Huang, Zheng, Zhu, & Yang, 2013). It has been proven to be highly cytotoxic to many cancer cell lines, but nothing is yet known of its mode of action in the cell (Cao, et al., 2007). To begin progress towards understanding the mode of action of ipomeoassin F, this study aimed to perform fluorescence imaging studies for the ultimate purpose of determining its cellular localization in MDA-MB-231 …

Impact Of Interdisciplinary Undergraduate Research In Mathematics And Biology On The Development Of A New Course Integrating Five Stem Disciplines, Lester Caudill, April L. Hill, Kathy Hoke, Ovidiu Z. Lipan

Department of Math & Statistics Faculty Publications

Funded by innovative programs at the National Science Foundation and the Howard Hughes Medical Institute, University of Richmond faculty in biology, chemistry, mathematics, physics, and computer science teamed up to offer first- and second-year students the opportunity to contribute to vibrant, interdisciplinary research projects. The result was not only good science but also good science that motivated and informed course development. Here, we describe four recent undergraduate research projects involving students and faculty in biology, physics, mathematics, and computer science and how each contributed in significant ways to the conception and implementation of our new Integrated Quantitative Science course, a …

Impact Of Interdisciplinary Undergraduate Research In Mathematics And Biology On The Development Of A New Course Integrating Five Stem Disciplines, Lester Caudill, April L. Hill, Kathy Hoke, Ovidiu Z. Lipan

Biology Faculty Publications

Funded by innovative programs at the National Science Foundation and the Howard Hughes Medical Institute, University of Richmond faculty in biology, chemistry, mathematics, physics, and computer science teamed up to offer first- and second-year students the opportunity to contribute to vibrant, interdisciplinary research projects. The result was not only good science but also good science that motivated and informed course development. Here, we describe four recent undergraduate research projects involving students and faculty in biology, physics, mathematics, and computer science and how each contributed in significant ways to the conception and implementation of our new Integrated Quantitative Science course, a …

Synthesis Of The Novel Crown Ether 1 ,9-Dioxa-4,6-Dithiacycloundecane, Cassie Booth

Capstone Research Projects

Attempts to produce novel crowns, incorporating a thioacetal fragment, were made via two synthetic pathways. Despite the well-established reactions found in path A (see figure 3), this method failed to produce the desired crown. Path B, a one-pot reaction originally designed to close rings via the addition of a thioacetal fragment, yielded an oily product that was purified with a silica gel column (48.3% yield). Initial analysis by 1H NMR showed a structure consistent with that of the desired crown (figure 2). Mass spectroscopy was used to verify product identity, confirming the creation of our target molecule 1 ,9-dioxa-4,6-dithiacycloundecane.

Predators And Life Histories Shape Lestes Damselfly Assemblages Along A Freshwater Habitat Gradient, Robby Stoks, Mark A. Mcpeek

Dartmouth Scholarship

Survey data from New England showed that assemblages of Lestes damselflies are organized along the entire gradient of pond permanence and predator presence. One assemblage occupies vernal ponds lacking large dragonfly predators and fish; four are largely confined to temporary ponds that typically contain dragonfly predators; one dominates fishless permanent ponds and lakes where dragonflies are the top predators; and one dominates permanent ponds and lakes where fish are the top predators. We determined the role of life history and predation in maintaining this striking pattern by conducting a series of transplant experiments in the field and a laboratory experiment …

Bible A Whole-Air Sampling As A Window On Asian Biogeochemistry, Felisa A. Smith, Scott Elliott, Donald R. Blake, Nikola J. Blake, Manvendra D. Dubey, F. Sherwood Rowland, Barkley C. Sive

Biology Faculty & Staff Publications

Asian trace gas and aerosol emissions into carbon, nitrogen, and other elemental cycles will figure prominently in near term Earth system evolution. Atmospheric hydrocarbon measurements resolve numerous chemical species and can be used to investigate sourcing for key geocarriers. A recent aircraft study of biomass burning and lightning (BIBLE A) explored the East Asian atmosphere and was unique in centering on the Indonesian archipelago. Samples of volatile organics taken over/between the islands of Japan, Saipan, Java, and Borneo are here examined as a guide to whole-air-based studies of future Asian biogeochemistry. The midlatitude onshore/offshore pulse and tropical convection strongly influence …

Piagetian Developmental Reasoning Levels Of High School Students In Differentiated First Year Chemistry Courses, Pamela Kay Brewer-Michael

Dissertations and Theses @ UNI

This research studied the developmental reasoning levels of students in three different first year high school chemistry courses as related to achievement defined by cumulative grade point average and course selection. The Lawson Test of Formal Operations modified by Roy Unruh and Bruce Perry at the University of Northern Iowa was used to determine cognitive developmental level of subjects. A consumer type chemistry course, a traditional high school chemistry course, and an honors course under consideration with Marshalltown Community College for credit status were the three courses utilized in this study. Data was collected in a classroom group setting over …

Micronutrients And Biological Patterns In Lake Mead, Hasan K. Qashu, Lorne G. Everett, J. S. Carlson, Bureau Of Reclamation

Publications (WR)

Progressive increases in concentration of dissolved solids in the Colorado River water from Lake Powell to Imperial Dam seem to alter plankton dynamics and biological productivity of the river. Also, changes in biological productivity and micronutrients concentrations occur within the same reservoir. Development of a digital simulation model to predict micronutrients concentrations and biological productivity is necessary for diagnosing changes in plankton population and effluent-carrying capacity of the system. The objectives of the study are: (1) to determine trace metal balance at different locations in Lake Mead, (2) to measure biological productivity and conduct plankton population counts at each sampling …