Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib, both lack HER2 selectivity, leading to off-target adverse events in patients. The development of HER2 mutation during treatment also hampers the progress of the treatment. We used a molecular hybridization strategy for structural optimizations, in conjunction with in vitro and in vivo drug-like property screening, to obtain a clinical candidate SPH5030. Overall, SPH5030 showed excellent activities against four frequent kinds of HER2 mutants and high relative HER2 selectivity compared with neratinib and pyrotinib, good pharmacokinetic characteristics with desirable bioavailabilities, and significant in vivo antitumor efficacy in xenograft mouse models, especially in a HER2 mutation A775_G776insYVMA xenograft mouse model with its potency much higher than those of neratinib and pyrotinib.
Monday, March 28, 2022
Friday, March 25, 2022
Bakker, A.; Kotsogianni, I.; Mirenda, L.; Straub, V.; Florea, B.; van den Berg, R.; Janssen, A.; Martin, N.; van der Stelt, M. ChemRxiv .
Phenotypic screening is a powerful approach to identify novel antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) infection, but elucidation of the targets responsible for antimicrobial activity is often challenging in the case of compounds with a polypharmacological mode-of-action. Here, we show that activity-based protein profiling maps the target interaction landscape of a series of 1,3,4-oxadiazole-3-ones, identified in a phenotypic screen to have high antibacterial potency against multidrug resistant S. aureus. In situ competitive and comparative chemical proteomics with a tailor-made activity-based probe, in combination with transposon and resistance studies, revealed several cysteine and serine hydrolases as relevant targets. Our data showcase oxadiazolones as novel antibacterial chemotype with a polypharmacological mode-of-action, in which FabH, FphC and AdhE play a central role.
Monday, March 21, 2022
Wednesday, March 16, 2022
Single Mutation on Trastuzumab Modulates the Stability of Antibody–Drug Conjugates Built Using Acetal-Based Linkers and Thiol-Maleimide Chemistry
Xhenti Ferhati, Ester Jiménez-Moreno, Emily A. Hoyt, Giulia Salluce, Mar Cabeza-Cabrerizo, Claudio D. Navo, Ismael Compañón, Padma Akkapeddi, Maria J. Matos, Noelia Salaverri, Pablo Garrido, Alfredo Martínez, Víctor Laserna, Thomas V. Murray, Gonzalo Jiménez-Osés, Peter Ravn, Gonçalo J. L. Bernardes, and Francisco Corzana
Journal of the American Chemical Society 2022
Antibody-drug conjugates (ADCs) are a class of targeted therapeutics used to selectively kill cancer cells. It is important that they remain intact in the bloodstream and release their payload in the target cancer cell for maximum efficacy and minimum toxicity. The development of effective ADCs requires the study of factors that can alter the stability of these therapeutics at the atomic level. Here, we present a general strategy that combines synthesis, bioconjugation, linker technology, site-directed mutagenesis, and modeling to investigate the influence of the site and microenvironment of the trastuzumab antibody on the stability of the conjugation and linkers. Trastuzumab is widely used to produce targeted ADCs because it can target with high specificity a receptor that is overexpressed in certain breast cancer cells (HER2). We show that the chemical environment of the conjugation site of trastuzumab plays a key role in the stability of linkers featuring acid-sensitive groups such as acetals. More specifically, Lys-207, located near the reactive Cys-205 of a thiomab variant of the antibody, may act as an acid catalyst and promote the hydrolysis of acetals. Mutation of Lys-207 into an alanine or using a longer linker that separates this residue from the acetal group stabilizes the conjugates. Analogously, Lys-207 promotes the beneficial hydrolysis of the succinimide ring when maleimide reagents are used for conjugation, thus stabilizing the subsequent ADCs by impairing the undesired retro-Michael reactions. This work provides new insights for the design of novel ADCs with improved stability properties.
Friday, March 11, 2022
Xincheng Lin, Jiawei Cheng, Yuming Wu, Yaoliang Zhang, Hailun Jiang, Jian Wang, Xuejun Wang, and Maosheng Cheng
ACS Medicinal Chemistry Letters 2022
Xie Wang, Zongtao Lin, Katelyn A. Bustin, Nate R. McKnight, William H. Parsons, and Megan L. MatthewsDOI: 10.1021/jacs.1c12748
Tuesday, March 8, 2022
Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands
Hong-Yi Zhao, Hai-Peng Wang, Yu-Ze Mao, Hao Zhang, Minhang Xin, Xiao-Xiao Xi, Hao Lei, Shuai Mao, Dong-Hui Li, and San-Qi ZhangDOI: 10.1021/acs.jmedchem.1c01827
Saturday, March 5, 2022
SP3-enabled Rapid and High Coverage Chemoproteomic Identification of Cell-State Dependent Redox-Sensitive Cysteines [@Keribackus]
Heta S. Desai,Tianyang Yan,Fengchao Yu,Alexander W. Sun,Miranda Villanueva,Alexey I. Nesvizhskii,Keriann M. Backus
Molecular & Cellular Proteomics, 2022
Proteinaceous cysteine residues act as privileged sensors of oxidative stress. As reactive oxygen and nitrogen species (ROS and RNS) have been implicated in numerous pathophysiological processes, deciphering which cysteines are sensitive to oxidative modification and the specific nature of these modifications is essential to understanding protein and cellular function in health and disease. While established mass spectrometry-based proteomic platforms have improved our understanding of the redox proteome, the widespread adoption of these methods is often hindered by complex sample preparation workflows, prohibitive cost of isotopic labeling reagents, and requirements for custom data analysis workflows. Here, we present the SP3-Rox redox proteomics method that combines tailored low cost isotopically labeled capture reagents with SP3 sample cleanup to achieve high throughput and high coverage proteome-wide identification of redox-sensitive cysteines. By implementing a customized workflow in the open-source FragPipe computational pipeline, we achieve accurate MS1-based quantitation, including for peptides containing multiple cysteine residues. Application of the SP3-Rox method to cellular proteomes identified cysteines sensitive to the oxidative stressor GSNO and cysteine oxidation state changes that occur during T cell activation.
Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]
Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...
Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable ProteomeKatharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
Discovery of Non-Cysteine-Targeting Covalent Inhibitors by Activity-Based Proteomic Screening with a Cysteine-Reactive ProbeYejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
Madeline E Kavanagh, Benjamin D Horning, Roli Khattri, Nilotpal Roy, Justine P Lu, Landon R Whitby, Jaclyn C Brannon, Albert Parker, Joel M ...