Article
Biochemistry & Molecular Biology
Thomas Lenz, Kai Stuehler
Summary: Chemical biology and the application of small molecules have been proven to be effective strategies for studying protein functions, and several tools have been developed to identify interactions between small molecules and target or non-target proteins. In this study, the use of cellular thermal shift assay (CETSA) and thermal proteome profiling (TPP) were explored to investigate the potential secondary effects of small molecule treatments, such as changes in post-translational modifications or protein-protein interactions (PPI).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Jeon-Kyung Kim, Min Sun Choi, Jae-Young Kim, Jun Sang Yu, Jeong In Seo, Hye Hyun Yoo, Dong-Hyun Kim
Summary: Treatment with Gingko biloba leaf extract (GLE) suppressed intestinal BCRP expression and increased plasma concentrations of sulfasalazine in mice, accompanied by a reduction in certain bacterial populations. There was a correlation between BCRP expression and gut microbiota composition, suggesting modulation of gut microbiota may impact drug transporter-mediated interactions.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Medicine, General & Internal
Peng Gao, Yan-Qing Liu, Wei Xiao, Fei Xia, Jia-Yun Chen, Li-Wei Gu, Fan Yang, Liu-Hai Zheng, Jun-Zhe Zhang, Qian Zhang, Zhi-Jie Li, Yu-Qing Meng, Yong-Ping Zhu, Huan Tang, Qiao-Li Shi, Qiu-Yan Guo, Ying Zhang, Cheng-Chao Xu, Ling-Yun Dai, Ji-Gang Wang
Summary: In this study, a CQ probe was designed using photo-affinity labeling and click chemistry-based functionalization, and a combined deconvolution strategy of ABPP and MS-CETSA was developed to identify the protein targets of CQ in an unbiased manner. The results showed that CQ can disrupt glycolysis and energy metabolism of malarial parasites through direct binding with key enzymes, suggesting a new mechanism of action for CQ.
MILITARY MEDICAL RESEARCH
(2022)
Article
Immunology
Amrita Chakrabarti, Chintam Narayana, Nishant Joshi, Swati Garg, Lalit C. Garg, Anand Ranganathan, Ram Sagar, Soumya Pati, Shailja Singh
Summary: This study chemically synthesized a library of glycoside derivatives and evaluated their inhibitory efficacy against Leishmania donovani. The results showed that Gly2 had the highest inhibitory activity against promastigotes and strong binding affinity towards Gp63. In addition to its lethal effects on infectivity and multiplication, Gly2 also enhanced complement-mediated lysis and showed effectiveness against PKDL strain.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Morena L. Sutter, Lara Console, Anne-Fleur Fahner, Sophia L. Samodelov, Zhibo Gai, Giuliano Ciarimboli, Cesare Indiveri, Gerd A. Kullak-Ublick, Michele Visentin
Summary: By studying the interaction mechanism between the human embryonic kidney OCT2 transporter and MPP+, it was found that disrupting the CARC/CRAC mirror code in the 5th putative transmembrane domain is sufficient to abolish the allosteric interaction between the two.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Aarti Kawatkar, Roger A. Clark, Lorna Hopcroft, Debora Ann Roaquin, Ronald Tomlinson, Andrea M. Zuhl, Gillian M. Lamont, Jason G. Kettle, Susan E. Critchlow, M. Paola Castaldi, Frederick W. Goldberg, Andrew X. Zhang
Summary: Lactic acid transport inhibition is pursued as a therapeutic approach for cancers. We identified and optimized compounds that inhibit intracellular lactic acid efflux and developed three assays to measure cellular target engagement. These data demonstrate the power of orthogonal chemical biology methods to determine cellular target engagement, particularly for proteins not readily amenable to traditional biophysical methods.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Alexey L. Chernobrovkin, Cindy Cazares-Koerner, Tomas Friman, Isabel Martin Caballero, Daniele Amadio, Daniel Martinez Molina
Summary: Targeted protein degradation is an area of interest that could offer improvements in dosing, side effects, drug resistance, and targeting undruggable proteins. Cellular thermal shift assay (CETSA) combined with mass spectrometry (MS) can assess compound-induced changes in thousands of proteins' stability simultaneously, helping to understand the mode of action of protein degraders and identify off-target effects. Monitoring both target engagement and efficacy in intact cells allows for correlation between binding to the protein of interest and ligases, and degrader-induced protein degradation.
Article
Oncology
Jeffrey J. Kooijman, Wilhelmina E. van Riel, Jelle Dylus, Martine B. W. Prinsen, Yvonne Grobben, Tessa J. J. de Bitter, Antoon M. van Doornmalen, Janneke J. T. M. Melis, Joost C. M. Uitdehaag, Yugo Narumi, Yusuke Kawase, Jeroen A. D. M. de Roos, Nicole Willemsen-Seegers, Guido J. R. Zaman
Summary: This study extensively evaluates and compares 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators. Through biochemical and cellular profiling, the study identifies certain kinase inhibitors as response markers for cancer treatment and suggests the potential of in vitro profiling in identifying new patient stratification markers. The study also highlights the importance of subtle biochemical targeting differences in explaining cellular activity differences between inhibitors acting through the same primary target.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Analytical
Suhuur Osman, Claus Bendtsen, Samantha Peel, Linda Yrlid, Daniel Muthas, John Simpson, Keith R. Willison, David R. Klug
Summary: The cellular thermal shift assay (CETSA) is widely used to study drug-target engagement, especially in early stage drug discovery. Single-cell CETSA can accurately count active FOXO1 molecules and observe its stability and destabilization in the presence of small molecule inhibitors. The successful use of the MAC chip for single-cell CETSA enables the study of precious clinical samples and underlying population heterogeneity in cellular systems.
ANALYTICAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Feng Deng, Noora Sjostedt, Mariangela Santo, Mikko Neuvonen, Mikko Niemi, Heidi Kidron
Summary: Drug-drug interactions (DDIs) can have a significant impact on the safety of medication use. This study aimed to identify inhibitors of the breast cancer resistance protein (BCRP) among a library of commonly used drugs and anticancer drugs. 75 drugs were found to strongly inhibit BCRP, with vemurafenib, dabigatran etexilate, and everolimus being the most potent inhibitors. These findings suggest that clinical studies are needed to examine whether these drugs cause BCRP-mediated DDIs in humans.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Sonali Mehendale-Munj, Shivangi Sawant
Summary: Breast Cancer Resistance Protein (BCRP) is an efflux transporter responsible for causing multidrug resistance. BCRP expels potent antineoplastic drugs, leading to resistance and failure in cancer treatment. The regulation and expression of BCRP play important roles in maintaining the balance of xenobiotics and nutrients, impacting cancer therapies.
CURRENT DRUG TARGETS
(2021)
Article
Medicine, Research & Experimental
Zhuo-Xun Wu, Qiuyan Mai, Yuqi Yang, Jing-Quan Wang, Hansu Ma, Leli Zeng, Zhe-Sheng Chen, Yihang Pan
Summary: Overexpression of ABCG2 transporter leads to resistance of cancer cells to GSK1070916, and combination with an ABCG2 inhibitor can restore the sensitivity of GSK1070916.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Chemistry, Medicinal
Kunyu Shi, Jifa Zhang, Enda Zhou, Jiaxing Wang, Yuxi Wang
Summary: This article summarizes the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities, and discusses prospective strategies for designing additional RIP1 therapeutic agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Agriculture, Multidisciplinary
Feiyan Chen, Chu Li, Huiying Cao, Hantao Zhang, Cai Lu, Ruimei Li, Zhu Zhu, Lin Chen, Yunan Zhao
Summary: The study identified adenylate kinase 5 (AK5) as a target protein of ginsenosides in the brain and revealed 20(S)-protopanaxadiol (PPD) as a small-molecule activator of AK5. PPD was found to increase AK5 activities, shedding light on the molecular mechanisms of ginseng pharmacological effects in the central nervous system (CNS) and potential development of AK5 activators.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Biochemical Research Methods
Prerna Malaney, Oscar Benitez, Xiaorui Zhang, Sean M. Post
Summary: RNA-binding proteins (RBPs) bind to RNA in a sequence-specific manner, and flexible linkers between structured RNA-binding domains play a crucial role. The contribution of unstructured regions to RBP function, including RNA binding and protein stability, is important but challenging to determine. Therefore, rapid and economical assays are needed to study the impact of these unstructured regions on RBPs function.
Article
Biochemistry & Molecular Biology
Huan Sun, Ka Yang, Xue Zhang, Yingxue Fu, Jay Yarbro, Zhiping Wu, Ping-Chung Chen, Taosheng Chen, Junmin Peng
Summary: Chemoproteomics is a crucial platform for studying the mode of action of compounds. This study presents a pooling strategy to enhance throughput and applies it to a drug library. The findings demonstrate that pooling chemoproteomics screening is an efficient method for dissecting the molecular targets of compound libraries.
Article
Chemistry, Medicinal
Andrew D. Huber, Yongtao Li, Wenwei Lin, Annalise N. Galbraith, Ashutosh Mishra, Shaina N. Porter, Jing Wu, Rebecca R. Florke Gee, Wei Zhuang, Shondra M. Pruett-Miller, Junmin Peng, Taosheng Chen
Summary: This study describes the discovery of a molecule, SJPYT-195, which can reduce the protein level of PXR by acting as a molecular glue degrader of GSPT1, a translation termination factor. The findings provide insights into the chemical determinants of drug-induced GSPT1 degradation and also present assays and cell models for the discovery of PXR degraders.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Pharmacology & Pharmacy
Shyaron Poudel, Andrew D. Huber, Taosheng Chen
Summary: PXR and CAR are ligand-activated transcription factors that regulate drug metabolizing enzymes and transporters. They not only play important roles in drug efficacy, toxicity, and interactions, but also respond to a wide range of stimuli and are implicated in various diseases. Recent research has provided new insights into their biology and potential clinical applications.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Chemistry, Medicinal
Anand Divakaran, Cole R. Scholtz, Huda Zahid, Wenwei Lin, Elizabeth C. Griffith, Richard E. Lee, Taosheng Chen, Daniel A. Harki, William C. K. Pomerantz
Summary: Targeted protein degradation is a powerful tool for controlling cellular protein concentrations. In this study, the researchers designed a selective inhibitor of the first BRD4 bromodomain and developed a selective degrader for BRD4. This approach allowed for specific degradation of BRD4 without inhibiting other BET family members such as BRD2/3.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Giridhar Sekar, Geetika Singh, Xingping Qin, Cristina D. Guibao, Brittany Schwam, Zintis Inde, Christy R. Grace, Weixing Zhang, P. Jake Slavish, Wenwei Lin, Taosheng Chen, Richard E. Lee, Zoran Rankovic, Kristopher Sarosiek, Tudor Moldoveanu
Summary: The small molecule SJ572946 selectively activates BAK over BAX, showing cytotoxic effects on cancer cells, and can be used in combination with other apoptotic inducers and BH3 mimetics.
Article
Multidisciplinary Sciences
Wenwei Lin, Andrew D. Huber, Shyaron Poudel, Yongtao Li, Jayaraman Seetharaman, Darcie J. Miller, Taosheng Chen
Summary: The promiscuity of ligand-binding in detoxification systems is beneficial for body protection but a challenge for drug development. Through X-ray crystallography, we found that expanding the ligand-binding pocket of the PXR receptor can enhance binding affinity. However, this expansion is an unfavorable event, and engineering ligands to avoid clashes with the receptor can reduce safety liabilities. Therefore, engineering the ligand-binding pocket of PXR can potentially improve drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Jennifer L. Kamens, Stephanie Nance, Cary Koss, Beisi Xu, Anitria Cotton, Jeannie W. Lam, Elizabeth A. R. Garfinkle, Pratima Nallagatla, Amelia M. R. Smith, Sharnise Mitchell, Jing Ma, Duane Currier, William C. Wright, Kanisha Kavdia, Vishwajeeth R. Pagala, Wonil Kim, LaShanale M. Wallace, Ji-Hoon Cho, Yiping Fan, Aman Seth, Nathaniel Twarog, John K. Choi, Esther A. Obeng, Mark E. Hatley, Monika L. Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E. Rubnitz, Junmin Peng, Taosheng Chen, Anang A. Shelat, R. Kiplin Guy, Tanja A. Gruber
Summary: Proteasome inhibition is found to be effective in KMT2Ar infant acute lymphoblastic leukemia, leading to the depletion of histone modifications and downregulation of KMT2A gene expression signature. A cohort of relapsed/refractory KMT2Ar patients treated with this approach showed a high overall response rate. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Giovanni Quarato, Luigi Mari, Nicholas J. Barrows, Mao Yang, Sebastian Ruehl, Mark J. Chen, Cliff S. Guy, Jonathan Low, Taosheng Chen, Douglas R. Green
Summary: The degradation of defective mitochondria is regulated by the ubiquitin-proteasome system and lysosomal activities, which play essential roles in maintaining cellular homeostasis. Activation of the PINK1-Parkin axis following mitochondrial damage triggers a BAX- and BAK-independent cytochrome c release process, leading to apoptosis mediated by APAF1 and caspase 9. This process is initiated by UPS-dependent outer mitochondrial membrane degradation and can be reversed by proteasome inhibitors. Autophagy machinery recruitment to the outer mitochondrial membrane protects cells from apoptosis by mediating the lysosomal degradation of dysfunctional mitochondria. The study highlights the major role of the autophagy machinery in counteracting abnormal noncanonical apoptosis and identifies autophagy receptors as key regulators of this process.
Article
Oncology
Mika B. Jekabsons, Mollie Merrell, Anna G. Skubiz, Noah Thornton, Sandra Milasta, Douglas Green, Taosheng Chen, Yan-Hong Wang, Bharathi Avula, Ikhlas A. Khan, Yu-Dong Zhou
Summary: Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. Flux analysis is necessary to conclusively establish phenotypes, as pathway fluxes depend on additional factors. This study assessed the metabolic phenotypes of breast cancer cell lines with different metastatic potentials, as well as lung and bone-homing lines, and found differences in ATP production, nutrient consumption, and anabolic fluxes.
CANCER & METABOLISM
(2023)
Review
Pharmacology & Pharmacy
Stefanie A. Baril, Tomoka Gose, John D. Schuetz
Summary: Over the past two decades, advancements in membrane protein structural biology have provided insights into how transporters move diverse substrates across membranes. This paper highlights the structure and function of ATP binding cassette/solute carrier transporters related to diseases and multidrug resistance, and their importance in clinical chemotherapeutic outcomes.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Multidisciplinary Sciences
Tomoka Gose, Heather M. Aitken, Yao Wang, John Lynch, Evadnie Rampersaud, Yu Fukuda, Medb Wills, Stefanie A. Baril, Robert C. Ford, Anang Shelat, Megan L. O' Mara, John D. Schuetz
Summary: This research reveals the mechanism of substrate selection by ABCG2, identifying a crucial residue N436 that acts as a discriminator for substrate recognition and is required for optimal inhibitor action.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Jie Fang, Shivendra Singh, Changde Cheng, Sivaraman Natarajan, Heather Sheppard, Ahmed Abu-Zaid, Adam D. Durbin, Ha Won Lee, Qiong Wu, Jacob Steele, Jon P. Connelly, Hongjian Jin, Wenan Chen, Yiping Fan, Shondra M. Pruett-Miller, Jerold E. Rehg, Selene C. Koo, Teresa Santiago, Joseph Emmons, Stefano Cairo, Ruoning Wang, Evan S. Glazer, Andrew J. Murphy, Taosheng Chen, Andrew M. Davidoff, Carolina Armengol, John Easton, Xiang Chen, Jun Yang
Summary: A improved MYC-driven hepatoblastoma-like murine model is developed and characterized in this study, which recapitulates the pathological features of embryonal type of hepatoblastoma and shows transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and CRISPR-Cas9 screening are used to identify distinct subpopulations of hepatoblastoma cells and druggable targets shared with human hepatoblastoma. The study also reveals genetic modifiers of chemotherapy response and suggests a potential therapeutic strategy for human hepatoblastoma.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Rebecca R. Florke Gee, Andrew D. Huber, Jing Wu, Richa Bajpai, Allister J. Loughran, Shondra M. Pruett-Miller, Taosheng Chen
Summary: This study identified FBXO44 as a novel E3 ligase for PXR, which regulates the protein abundance of PXR and has downstream effects on CYP3A4 levels and drug-drug interactions.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Biotechnology & Applied Microbiology
Ping Zhang, Harindra E. Amarasinghe, Justin P. Whalley, Chwen Tay, Hai Fang, Gabriele Migliorini, Andrew C. Brown, Alice Allcock, Giuseppe Scozzafava, Phalguni Rath, Benjamin Davies, Julian C. Knight
Summary: This study systematically investigates the acute innate immune response to endotoxin in human macrophages and compares it with endotoxin tolerance. It provides insights into the regulatory networks involved in enhancer activities and biological processes, and reveals the importance of context-specific macrophage enhancers in gene regulation and interpreting disease associations. The study also identifies specific differential enhancer regions and links genetic variants with molecular and cellular functions.