Review
Pharmacology & Pharmacy
Yinrong Wu, Zichao Yang, Kui Cheng, Huichang Bi, Jianjun Chen
Summary: Immunotherapy has revolutionized cancer treatment, with current therapies mostly based on antibodies. However, these therapies have limitations in terms of pharmacokinetics and immunogenicity. To overcome these limitations, researchers have focused on developing small molecule-based immunotherapy. This review provides an overview of the progress in small molecule-based immunomodulators for cancer therapy, including targeting PD-1/PD-L1, chemokine receptors, STING, TLR, etc. The importance of combining small molecule-based immunomodulators with therapeutic antibodies is also highlighted.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Microbiology
Bradley Benjamin, Yehuda Goldgur, Nikolaus Jork, Henning J. J. Jessen, Beate Schwer, Stewart Shuman
Summary: The fission yeast Schizosaccharomyces pombe phosphate regulon is sensitive to the level of the inositol pyrophosphate signaling molecule 1,5-IP8. The enzyme Asp1, consisting of a kinase domain and a pyrophosphatase domain, plays a crucial role in determining the dynamics of IP8. Crystal structures of the Asp1 kinase domain reveal its conformational changes upon ligand binding and its substrate specificity. Wild-type Asp1 kinase can utilize N-6-benzyl-ATP as a phosphate donor.
Review
Biochemistry & Molecular Biology
Roberta Ettari, Santo Previti, Carla Di Chio, Maria Zappala
Summary: Malaria is a serious global public health issue, with chemotherapy being the only current treatment method due to lack of effective vaccine. However, the resistance to antimalarial drugs poses a challenge to the current therapeutic regimen. Therefore, the search for new drug targets is a pressing priority.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Vincent Chaptal, Veronica Zampieri, Benjamin Wiseman, Cedric Orelle, Juliette Martin, Kim-Anh Nguyen, Alexia Gobet, Margot Di Cesare, Sandrine Magnard, Waqas Javed, Jad Eid, Arnaud Kilburg, Marine Peuchmaur, Julien Marcoux, Luca Monticelli, Martin Hogbom, Guy Schoehn, Jean-Michel Jault, Ahcene Boumendjel, Pierre Falson
Summary: This study resolved three outward-facing conformations of BmrA, a multidrug ABC transporter, using x-ray crystallography and cryo-electron microscopy. It was found that two R6G molecules bind to the drug-binding cavity, inducing a rearrangement of TM1-2 and highlighting local flexibility. Simulations showed that in the absence of R6G, the cavity quickly closed after drug release, while in the presence of R6G, the cavity remained open.
Article
Multidisciplinary Sciences
Neil J. Rzechorzek, Simone Kunzelmann, Andrew G. Purkiss, Mariana Silva Dos Santos, James I. MacRae, Ian A. Taylor, Kasper Fugger, Stephen C. West
Summary: This study presents the crystal structures and catalytic process of DNPH1, providing important insights for inhibitor design. Inactivation of DNPH1 increases the incorporation of hmdU into DNA, making BRCA-deficient cells more sensitive to PARP inhibitors.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Fan Yang, Zhigang Hu, Zhigang Guo
Summary: DNA damage repair is crucial for maintaining genomic stability and integrity, and FEN1 plays a critical role in this process. Abnormal expression or mutation of FEN1 is associated with various diseases, including cancers, making it a therapeutic target for cancer treatment. Small-molecule compounds targeting FEN1 have been developed and show promise in cancer therapy.
Article
Multidisciplinary Sciences
Na Feng, Han Feng, Sheng Wang, Avinash S. Punekar, Rudolf Ladenstein, Da-Cheng Wang, Qinghua Zhang, Jingjin Ding, Wei Liu
Summary: Heat shock factors 1 (HSF1) and 2 (HSF2) are key regulators in maintaining cellular proteostasis and mediating cell differentiation and development. This study presents co-crystal structures of human HSF1 and HSF2 trimers bound to DNA, revealing a triangular arrangement of the DNA-binding domains (DBDs) and potential factors contributing to differential specificity between HSF1 and HSF2.
Review
Medicine, General & Internal
Jianjing Lin, Shicheng Jia, Weifei Zhang, Mengyuan Nian, Peng Liu, Li Yang, Jianwei Zuo, Wei Li, Hui Zeng, Xintao Zhang
Summary: Osteoarthritis is a degenerative disease characterized by joint pain, caused by factors such as fibrosis, chapping, ulcers, and loss of articular cartilage. Traditional treatments only delay its progression, while small molecule inhibitors targeting proteins show promising effects in managing osteoarthritis. This review examines small molecule inhibitors targeting various proteins and discusses disease-modifying osteoarthritis drugs based on them, providing valuable insights for the treatment of osteoarthritis.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Fatemeh Emadi, Jimma Lenjisa, Laychiluh Mekonnen, Shudong Wang
Summary: As the fifth pillar of cancer treatment, immunotherapy has revolutionized therapeutic strategies by focusing on the host's immune system. The discovery of immune-modulatory effects for kinase inhibitors has opened up new possibilities in this approach, as these small molecule inhibitors not only directly target essential proteins for tumor survival and proliferation, but also stimulate immune responses against malignant cells.
DRUG DISCOVERY TODAY
(2023)
Review
Infectious Diseases
Virgyl Camberlein, Gwenaelle Jezequel, Joerg Haupenthal, Anna K. H. Hirsch
Summary: LasB, a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa, has become a key target in the development of novel antivirulence agents. This review provides an overview of the structure of its active site and a summary of the disclosed P. aeruginosa LasB inhibitors, with a specific focus on their binding modes and strategies for targeting LasB by small molecules.
Article
Multidisciplinary Sciences
Michal Zielinski, Jonathan Blanchet, Sophia Hailemariam, Albert M. Berghuis
Summary: This study presents the structural and kinetic characteristics of a promiscuous aminoglycoside acetyltransferase AAC(3)-IIIa and investigates the binding mode of aminoglycoside antibiotics and their effects on various aminoglycosides.
Review
Pharmacology & Pharmacy
Niels Heersche, G. D. Marijn Veerman, Mirjam de With, Sander Bins, Yehuda G. Assaraf, Anne-Marie C. Dingemans, Ron H. N. van Schaik, Ron H. J. Mathijssen, Frank G. A. Jansman
Summary: Small-molecule kinase inhibitors play a crucial role in the treatment of non-small cell lung cancer patients with genetic driver mutations. However, the treatment efficacy and drug resistance vary greatly among patients, which can be attributed to factors such as oral administration, drug interactions, and germline variations.
DRUG RESISTANCE UPDATES
(2022)
Article
Chemistry, Medicinal
Qiuyao Huang, Yan Zhong, Bingbing Li, Shumin Ouyang, Lin Deng, Jianshan Mo, Shuo Shi, Nan Lv, Ruibo Wu, Peiqing Liu, Wenhao Hu, Xiaolei Zhang, Yuanxiang Wang
Summary: In this study, we identified a number of highly potent and selective STAT3 inhibitors, with compound 39 showing promising inhibition of phosphorylation of STAT3 and suppression of downstream signaling pathways. Moreover, compound 39 demonstrated significant effects on cell growth, migration, and invasion of TNBC cells, as well as tumor growth inhibition in both cell line-derived and patient-derived xenograft models in mice.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Chao Zhang, Qian Xie, Chi Cheong Wan, Zhe Jin, Chun Hu
Summary: HIV-1 integrase plays a crucial role in HIV-1 treatment, but issues like drug resistance require further research. This review discussed the structure, function, and recent advances in small-molecule inhibitors of HIV-1 integrase.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Melika Loriamini, Melissa M. Lewis-Bakker, Kayluz Frias Boligan, Siming Wang, Mairead B. Holton, Lakshmi P. Kotra, Donald R. Branch
Summary: In our initial publication, we demonstrated that small molecules can inhibit phagocytosis based on in vitro testing of over 200 compounds. We found four hit molecules with pyrazole core structure in a chemical library screening. Further evaluation resulted in the selection of two lead compounds with negligible toxicity and high efficacy in inhibiting phagocytosis. The rational development of these discoveries will lead to the selection of a lead compound(s) for pre-clinical evaluation through independent synthesis and in vivo activities.