Article
Microbiology
Travis Chia, Tomofumi Nakamura, Masayuki Amano, Nobutoki Takamune, Masao Matsuoka, Hirotomo Nakata
Summary: ACAi-028, a small molecule identified through in vitro screening, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of the HIV-1 capsid. It interacts with specific amino acid residues in the CA-NTD pocket, demonstrating anti-HIV-1 activity by affecting core disassembly and stability. These findings suggest ACAi-028 as a promising CA inhibitor for HIV-1 treatment.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Zhenlong Yu, Jian Gao, Xiaolei Zhang, Yulin Peng, Wenlong Wei, Jianrong Xu, Zhenwei Li, Chao Wang, Meirong Zhou, Xiangge Tian, Lei Feng, Xiaokui Huo, Min Liu, Mingliang Ye, De-an Guo, Xiaochi Ma
Summary: In this study, Shikonin (SHK) is identified as a potential inhibitor of the IKK beta/NEMO complex. It disrupts the stability of the complex and significantly impairs the proliferation of colorectal cancer cells.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Sama Shamloo, Andreas Kloetgen, Stavroula Petroulia, Kathryn Hockemeyer, Sonja Sievers, Aristotelis Tsirigos, Ioannis Aifantis, Jochen Imig
Summary: The incidence of melanoma, a commonly occurring cancer, has been increasing. Advanced-stage melanoma patients have poor prognoses compared to earlier stages. Targeted therapies for advanced-stage melanomas have been effective, but patients develop BRAF-inhibitor resistance. This resistance is mainly driven by mutations in the MAPK pathway, but other factors such as lncRNAs are still poorly understood. A comprehensive study on lncRNA expression and screening for BRAF inhibitor resistance can provide valuable insights for potential combinatorial treatment approaches.
Article
Medicine, Research & Experimental
Qi Liu, Weilin Yuan, Yuwei Yan, Bing Jin, Mengke You, Tianqi Liu, Mingchun Gao, Jin Li, Priyanka Gokulnath, Gururaja Vulugundam, Guoping Li, Bin Xu, Junjie Xiao
Summary: Muscle atrophy is a debilitating condition without effective pharmacological treatment. In this study, we developed a novel small-molecule inhibitor targeting miR-29b, which showed promising results in attenuating muscle atrophy induced by various stressors in both cell culture and animal models. This small molecule has the potential to serve as a therapeutic agent for muscle atrophy.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2023)
Article
Pharmacology & Pharmacy
Qian Zhao, Teng Wang, Huanhuan Wang, Cheng Cui, Wen Zhong, Diyi Fu, Wanlin Xi, Lu Si, Jun Guo, Ying Cheng, Hongqi Tian, Pei Hu
Summary: This study investigated the pharmacokinetics of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma. The results showed that tunlametinib was rapidly absorbed and eliminated at a medium speed after drug withdrawal. There was a general dose-proportional increase in pharmacokinetic body exposure. Slight accumulation was found after multiple oral doses. The findings provide guidance for the dosing regimen of tunlametinib.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hongbo Zhang, Yu Xia, Chunqiu Yu, Huijie Du, Jinchang Liu, Hui Li, Shihui Huang, Qihua Zhu, Yungen Xu, Yi Zou
Summary: The blockade of the PD-1/PD-L1 interaction is a major focus in cancer immunotherapy, with several monoclonal antibodies showing promising outcomes. However, limitations with mAbs have led to the development of small-molecule inhibitors of PD-1/PD-L1 pathways. A new series of inhibitors targeting the PD-1/PD-L1 interaction have been discovered, with compound A9 showing the most promising inhibitory activity and binding affinity, as well as the ability to promote the production of interferon-gamma.
Article
Immunology
Yuanyuan Wang, Tingxuan Gu, Xueli Tian, Wenwen Li, Ran Zhao, Wenqian Yang, Quanli Gao, Tiepeng Li, Jung-Hyun Shim, Chengjuan Zhang, Kangdong Liu, Mee-Hyun Lee
Summary: PDI-1, a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity by relieving T cell exhaustion induced by PD-1/PD-L1. It enhances T cell cytotoxicity towards cancer cells, increases inflammatory cytokine production, and reduces tumor growth in mouse models. The anti-tumor effect of PDI-1 is comparable to that of the anti-PD-L1 antibody atezolizumab, suggesting small molecule inhibitors of PD-1/PD-L1 may be an effective immune checkpoint inhibitor alternative to monoclonal antibodies.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Paul Tawa, Lei Zhang, Essam Metwally, Yan Hou, Mark A. McCoy, W. Michael Seganish, Rumin Zhang, Emily Frank, Payal Sheth, Jennifer Hanisak, Christopher Sondey, David Bauman, Aileen Soriano
Summary: cGMP-dependent protein kinase (PKG) is an important drug target for cardiovascular diseases. In this study, a novel series of activators were identified that can directly bind and enhance the kinase activity of PKG1. These activators mimic the effect of cGMP on PKG1 by modulating its kinetic parameters and binding affinity for cGMP. They act by binding to an allosteric site near the regulatory domain of PKG1.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yaxin Li, Cody M. Orahoske, Werner J. Geldenhuys, Asmita Bhattarai, Abboud Sabbagh, Viharika Bobba, Fatma M. Salem, Wenjing Zhang, Girish C. Shukla, Justin D. Lathia, Bingcheng Wang, Bin Su
Summary: Compound I, an HSP27 inhibitor, effectively induces AR degradation in GBM cells via the proteasomal pathway, selectively inhibiting the growth of AR-overexpressed GBM cells. These findings suggest that targeting HSP27 to induce AR degradation in GBM shows promise as a novel treatment approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Peter S. Dragovich, Wolfgang Haap, Melinda M. Mulvihill, Jean-Marc Plancher, Antonia F. Stepan
Summary: This article describes the origin of small-molecule leads pursued by the independent research organizations Roche and Genentech from 2009 to 2020. The identified chemical series were derived from various lead-finding methods, including public information, high-throughput screening, fragment-based design, DNA-encoded library technology, use of legacy internal data, in-licensing, and de novo design. The article discusses the translation of these leads into in vivo tool compounds and development candidates, as well as their associated biological target classes and therapeutic areas. The analysis identifies important trends and commonalities and differences across the two organizations.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Namkyoung Kim, Injae Shin, Jiwon Lee, Eunhye Jeon, Younghoon Kim, Seongshick Ryu, Eunhye Ju, Wonjeong Cho, Taebo Sim
Summary: This study identified six pyrimido[4,5-d]pyrimidin-2-one derivatives with highly potent anti-proliferative activities against melanoma cells harboring BRAF class I/II/III mutations. The novel compound SIJ1777 showed the most potent effects and outperformed vemurafenib and PLX8394 in inhibiting the proliferation of melanoma cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Tony Eight Lin, Li-Chin Sung, Min-Wu Chao, Min Li, Jia-Huei Zheng, Tzu-Ying Sung, Jui-Hua Hsieh, Chia-Ron Yang, Hsueh-Yun Lee, Er-Chieh Cho, Kai-Cheng Hsu
Summary: This article reports the identification of a novel noncovalent BTK inhibitor that showed favorable inhibitory activity in solid tumor cell lines, suggesting its potential for targeting BTK malignant tumors.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Okki Cho, Joong-Woon Lee, Han -Sol Kim, Young-Jin Jeong, Tae-Hwe Heo
Summary: In this study, the researchers investigated the inhibitory effects of chelerythrine (CHE) on IL-2 activity and its potential as an anticancer agent. They found that CHE selectively inhibited the interaction between IL-2 and IL-2R alpha and directly bound to IL-2. CHE inhibited the proliferation and signaling of CTLL-2 cells, suppressed IL-2 activity in different immune cells, and prevented the conversion of CD4+ T cells into regulatory T cells. In mouse models, CHE reduced tumor growth, upregulated the expression of IFN-gamma and cytotoxic molecules, and synergistically increased antitumor activity when combined with a PD-1 inhibitor.
Review
Chemistry, Medicinal
Lixin Zhou, Tianyu Wang, Kuojun Zhang, Xiangyu Zhang, Sheng Jiang
Summary: Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine protein kinase that negatively regulates T cells, B cells, and dendritic cells-mediated immune responses. It plays a role in cellular processes such as immune cell activation, differentiation, proliferation, adhesion, and apoptosis. HPK1 is associated with the occurrence and development of human malignant tumors, making it a promising target for cancer immunotherapies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Artem Gridnev, Subhajit Maity, Jyoti R. R. Misra
Summary: The study identified a small molecule inhibitor, JM7, which can indirectly inhibit the activity of YAP by targeting the palmitoylation of TEAD. Inhibiting TEAD palmitoylation destabilizes TEAD and inhibits YAP's oncogenic activity, leading to impaired proliferation and migration of cancer cells.
FRONTIERS IN ONCOLOGY
(2022)
Article
Genetics & Heredity
Jonathan Lenz, Robert Liefke, Julianne Funk, Samuel Shoup, Andrea Nist, Thorsten Stiewe, Robert Schulz, Yumiko Tokusumi, Lea Albert, Hartmann Raifer, Klaus Foerstemann, Olalla Vazquez, Tsuyoshi Tokusumi, Nancy Fossett, Alexander Brehm
Summary: The U-shaped gene regulator in Drosophila coordinates the activation and inactivation of three differentiation-related gene groups to modulate lipid metabolism, promote cell division, and maintain a progenitor state. This regulation is carried out by different U-shaped protein isoforms and their associated co-factors, such as the dNuRD complex. The U-shaped/NuRD complex specifically contributes to the repression of lineage-specific genes, demonstrating a mechanism for specific and concerted modulation of gene expression during cellular differentiation.
Article
Oncology
Franziska Liss, Miriam Frech, Ying Wang, Gavin Giel, Sabrina Fischer, Clara Simon, Lisa Marie Weber, Andrea Nist, Thorsten Stiewe, Andreas Neubauer, Andreas Burchert, Robert Liefke
Summary: The study identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans, demonstrating its critical role in regulating key signaling molecules, cell proliferation, and patient prognosis. High IRF8 expression is associated with poorer outcomes, indicating IRF8 as a potential biomarker and molecular target for a subset of AML cases.
Article
Multidisciplinary Sciences
Bastian Stielow, Yuqiao Zhou, Yinghua Cao, Clara Simon, Hans-Martin Pogoda, Junyi Jiang, Yanpeng Ren, Sabrina Keita Phanor, Iris Rohner, Andrea Nist, Thorsten Stiewe, Matthias Hammerschmidt, Yang Shi, Martha L. Bulyk, Zhanxin Wang, Robert Liefke
Summary: SAMD1 is a protein that can bind to unmethylated CpG islands, with a unique domain that interacts with DNA to regulate transcription repression at CGIs by modulating H3K4me2 and H3K4me3 levels. Its absence can lead to impaired cell differentiation processes.
Review
Oncology
Oleg Timofeev, Thorsten Stiewe
Summary: p53 is a DNA-binding protein that activates genes to suppress cancer cells, and its mutations, including cooperativity mutations, can lead to tumorigenesis. Understanding the structural basis of p53's DNA binding cooperativity is important for cancer therapy, as it plays a critical role in controlling cell fate decisions and tumor suppression. Research on p53 has provided insights into its function and potential personalized treatments for cancer patients with cooperativity mutations.
Article
Medical Ethics
Katharina Beier, Alfred Simon, Michael P. Schon
ETHIK IN DER MEDIZIN
(2022)
Article
Biochemistry & Molecular Biology
Boris Klimovich, Nastasja Merle, Michelle Neumann, Sabrina Elmshaeuser, Andrea Nist, Marco Mernberger, Daniel Kazdal, Albrecht Stenzinger, Oleg Timofeev, Thorsten Stiewe
Summary: Partial loss-of-function mutations of p53 play a significant role in tumorigenesis, leading to mutant p53 protein accumulation similar to hotspot mutations. Unlike p53 loss, these mutations enhance apoptotic chemotherapy response and improve survival rates in a therapy context.
Article
Oncology
Boris Klimovich, Laura Meyer, Nastasja Merle, Michelle Neumann, Alexander M. Konig, Nikolaos Ananikidis, Corinna U. Keber, Sabrina Elmshauser, Oleg Timofeev, Thorsten Stiewe
Summary: The study found that the p53 variant E177R has the potential to inhibit proliferation and viability, induce immune cell infiltration, and trigger cancer regression in p53-deficient leukemia and lymphomas. Even the low-level activity of E177R is detrimental to cancer growth, indicating a high dependence of cancer cells on the absence of p53.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Cell Biology
Pierfrancesco Polo, Niklas Gremke, Thorsten Stiewe, Michael Wanzel
Summary: Autophagy allows cells to tolerate energy stress and reduce the cytotoxic effects of anticancer drugs. The autophagy pathway shows robustness and resilience even with the copy number loss of key autophagy genes in cancer patients. Therefore, autophagy defects may indicate a metabolically vulnerable cancer state and provide a therapeutic opportunity.
Article
Biochemistry & Molecular Biology
Viktoria E. M. Schindler, Fahd Alhamdan, Christian Preusser, Lukas Hintz, Bilal Alashkar Alhamwe, Andrea Nist, Thorsten Stiewe, Elke Pogge von Strandmann, Daniel P. Potaczek, Clemens Thoelken, Holger Garn
Summary: This study aimed to characterize the profiles of vesicular miRNA released by bronchial epithelial cells from healthy and asthmatic subjects. The results showed that EVs were released differently depending on the cell side, and the miRNA profiles were significantly affected by disease conditions.
Article
Biology
Clara Simon, Bastian Stielow, Andrea Nist, Iris Rohner, Lisa Marie Weber, Merle Geller, Sabrina Fischer, Thorsten Stiewe, Robert Liefke
Summary: Hepatocellular carcinoma (HCC) is a common and deadly cancer. This study investigates the role of the CpG island regulator SAMD1 in liver cancer cells. The researchers found that SAMD1 is highly expressed in liver cancer tissues and deleting it leads to abnormal gene regulation and a better prognosis gene signature. SAMD1 appears to play a crucial role in promoting cell proliferation in HCC cells.
Article
Biochemistry & Molecular Biology
Tobias Friedrich, Francesca Ferrante, Leo Pioger, Andrea Nist, Thorsten Stiewe, Jean-Christophe Andrau, Marek Bartkuhn, Benedetto Daniele Giaimo, Tilman Borggrefe
Summary: The study investigates the role of transcription factor RBPJ in the Notch signaling pathway. It is found that RBPJ not only participates in the Notch co-activator complex, but also functions as a repressor, playing a crucial role in regulating Notch target genes.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Aleksandra Lopez Krol, Hannah P. Nehring, Felix F. Krause, Anne Wempe, Hartmann Raifer, Andrea Nist, Thorsten Stiewe, Wilhelm Bertrams, Bernd Schmeck, Maik Luu, Hanna Leister, Ho-Ryun Chung, Uta-Maria Bauer, Till Adhikary, Alexander Visekruna
Summary: This study indicates that lactate can induce changes in the gene expression program of Th17 cells by modulating their metabolism and epigenetic status, resulting in a shift in their function.
Review
Biology
Siavash Mansouri, Daniel Heylmann, Thorsten Stiewe, Michael Kracht, Rajkumar Savai
Summary: Lung cancer classification and treatment have been revolutionized by advances in understanding driver mutations and the introduction of tumor microenvironment (TME)-associated immune checkpoint inhibitors. However, many patients develop resistance to these therapies due to specific driver mutations that favor an immunosuppressive TME phenotype. Clinical studies investigating the crosstalk between driver mutations and the TME immune profile hold promise for better treatment choices and personalized medicine.
Article
Cell Biology
Eva Romanovsky, Klaus Kluck, Iordanis Ourailidis, Michael Menzel, Susanne Beck, Markus Ball, Daniel Kazdal, Petros Christopoulos, Peter Schirmacher, Thorsten Stiewe, Albrecht Stenzinger, Jan Budczies
Summary: TP53 is the most frequently mutated gene in human cancer. mRNA expression analysis in 24 cancer types revealed consistent expression patterns, differential gene expression associated with different TP53 mutation types, and cancer type-specific gene expression and immune infiltration patterns. These findings support the evaluation of TP53 mutations as predictive markers for immunotherapy and targeted therapies.
CELL DEATH DISCOVERY
(2023)
Article
Health Care Sciences & Services
Caroline Beutner, Anja Lipschik, Luise Erpenbeck, Jason Holsapple, Michael P. Schoen, Hedwig Stanisz
Summary: The COVID-19 pandemic has severely disrupted the work-family balance of medical doctors, primarily due to insufficient childcare. Doctors feel that the measures taken by local governments are not sufficient, particularly placing the professional development of female doctors at risk. Proper and flexible childcare is essential for the career advancement of doctors.