Article
Chemistry, Medicinal
Hong-Yi Zhao, Hai-Peng Wang, Yu-Ze Mao, Hao Zhang, Minhang Xin, Xiao-Xiao Xi, Hao Lei, Shuai Mao, Dong-Hui Li, San-Qi Zhang
Summary: This study developed proteolysis targeting chimeras (PROTACs) targeting EGFR mutants by optimizing covalent EGFR ligands to overcome drug resistance in non-small-cell lung cancer (NSCLC). The covalent PROTAC CP17 was discovered to be a highly potent degrader against EGFRL858R/T790M and EGFRdel19 with excellent selectivity. Mechanism investigation showed that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be effective for designing PROTACs targeting EGFRL858R/T790M.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Paige E. Solomon, Colton J. Bracken, Jacqueline A. Carozza, Haoqing Wang, Elizabeth P. Young, Alon Wellner, Chang C. Liu, E. Alejandro Sweet-Cordero, Lingyin Li, James A. Wells
Summary: In this study, VH single-domain antibodies against ENPP1 were generated using phage and yeast display. A VH domain was discovered that allosterically inhibited the hydrolysis of cGAMP and ATP. Furthermore, the VH domain was engineered into multispecific formats and immunotherapies, showing potent cellular activity.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Genetics & Heredity
Jingkun Yi, Rucong Liu, Yu Liu, Ting Guo, Yang Li, Yuan Zhou
Summary: Recent studies have identified the important role of m6A modification of mRNA in cancer progression. Through integrative analysis of transcriptome data, potential m6A-targeted drugs were discovered, and the inhibitory effects of two drugs on cancer cell proliferation were experimentally verified.
Article
Chemistry, Multidisciplinary
Yumi Koga, Eileen M. Hoang, Yongho Park, Alexander F. A. Keszei, Jason Murray, Sichen Shao, Brian B. Liau
Summary: Cycloheximide (CHX) has been used for over half a century to study protein synthesis, but its rapid reversibility often leads to incomplete translation inhibition, prompting the need for improved reagents. The concise synthesis of C13-amide-functionalized CHX derivatives with increased potencies towards protein synthesis inhibition has been reported. These new compounds, particularly C13-aminobenzoyl CHX, have shown superior performance in ribosome profiling experiments, allowing for more effective capture of ribosome conformations.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Nicole L. Richardson, Laura J. O'Malley, Daniel Weissberger, Anthony Tumber, Christopher J. Schofield, Renate Griffith, Nicole M. Jones, Luke Hunter
Summary: A virtual high throughput screen based on pharmacophore was used to identify novel potential inhibitors of human PHD2, resulting in the discovery of two moderately potent new inhibitors with protective activity in neuroblastoma cells. These compounds show promise to be developed into clinically useful neuroprotective agents in the future.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Peiyuan Gao, Amity Andersen, Jonathan Sepulveda, Gihan U. Panapitiya, Aaron Hollas, Emily G. Saldanha, Vijayakumar Murugesan, Wei Wang
Summary: Aqueous organic redox flow batteries provide an environmentally friendly and safe method for large-scale energy storage, and its performance depends on the solubility of the redox-active molecules in water. Predicting solubility in water remains a challenge in chemistry, but machine learning models offer a solution. This article presents a comprehensive open-access organic molecular database that contains 12,000 molecules, providing a foundation for future development of AI-based solubility prediction models.
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.
Article
Multidisciplinary Sciences
Xin Liu, Ye Zhang, Lucas D. Ward, Qinghong Yan, Tanggis Bohnuud, Rocio Hernandez, Socheata Lao, Jing Yuan, Fan Fan
Summary: A proteomics-based platform was developed to assess the abundance of off-target proteins, with 2813 proteins selected as the off-target proteome (SOTP) based on genetics and pharmacology evidence. Mass spectrometry was then used to identify 1828 proteins from the SOTP in 4 human cell lines.
SCIENTIFIC REPORTS
(2021)
Article
Pharmacology & Pharmacy
Teresa Lopes Gomes, Virginia de Oliveira-Marques, Richard John Hampson, Antonio Jacinto, Luciana Vieira de Moraes, Rui Goncalo Martinho
Summary: Tight junctions are formed by proteins that seal the intercellular space and control the permeability of epithelia. This study focuses on finding compounds that reinforce the epithelial barrier and developed a screening platform to identify compounds that modulate the expression of Par-6, a protein involved in tight junction assembly. Six compounds were tested and two of them (myricetin and quercetin) were shortlisted for further development.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
William Mangione, Zackary Falls, Ram Samudrala
Summary: This study utilized computational analysis to identify small molecule inhibitors for the treatment of SARS-CoV-2 and COVID-19. They optimized drug candidate prediction pipelines and published ranked candidate lists at the beginning of the pandemic. Subsequent studies confirmed the efficacy of their predictions, highlighting the platform's ability to respond rapidly to emergent pathogens and accurately describe compound behavior in biological systems.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Martin D. Gelenter, Aurelio J. Dregni, Pu Duan, Mei Hong
Summary: The researchers have designed mutated forms of glucagon that can resist fibrillization for weeks at pharmaceutical concentrations, exhibiting significantly slower fibrillization under stressed conditions with high salt concentrations and agitation.
Article
Biochemical Research Methods
Haiyan Gu, Rui Shi, Chen Xu, Wenhao Lv, Xueyin Hu, Canxin Xu, Yuanbo Pan, Xiahong He, Aiguo Wu, Juan Li
Summary: In this study, an EGFR-targeting nanoliposome (LTL@Rh2@Lipo-GE11) using ginsenoside Rh2 as a wall material was developed for targeted therapy of TNBC. The nanoliposomes demonstrated high specificity to MDA-MB-231 cells that expressed a high level of EGFR, leading to strong inhibitory effects on the growth and migration of TNBC. These results suggest that LTL@Rh2@Lipo-GE11 is a promising candidate for targeted therapy of TNBC.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Tatsuo Akaki, Yuki Bessho, Takashi Ito, Shingo Fujioka, Minoru Ubukata, Genki Mori, Kenji Yamanaka, Takuya Orita, Satoki Doi, Tomoko Iwanaga, Kazutaka Ikegashira, Yoshiji Hantani, Isao Nakanishi, Tsuyoshi Adachi
Summary: This study utilized a fragment-based lead discovery approach to identify inhibitors against PDHKs with novel chemotypes, providing new structural insights into the deep binding interactions at the ATP site. The research successfully generated lead compounds with high selectivity and efficiency, opening up a new direction for the development of PDHKs inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Rit Pratik Mishra, Surbhi Gupta, Anurag Singh Rathore, Gaurav Goel
Summary: A multi-level virtual screening protocol is developed to identify lead molecules that can inhibit insulin aggregation. The protocol involves multiple steps, including screening the inactives database, docking and molecular dynamics simulations, and experimental validation. Riboflavin is identified as the most effective lead molecule for inhibiting insulin aggregation.
MOLECULAR PHARMACEUTICS
(2022)
Review
Chemistry, Multidisciplinary
Jason E. Camp, Ben W. Greatrex
Summary: This review discusses the conversion of levoglucosone (LGO) into biologically active compounds and future research directions related to this platform molecule.
FRONTIERS IN CHEMISTRY
(2022)
Correction
Chemistry, Medicinal
Mandeep K. Mann, Carlos A. Zepeda-Velazquez, Hector Gonzalez-Alvarez, Aiping Dong, Taira Kiyota, Ahmed M. Aman, Peter Loppnau, Yanjun Li, Brian Wilson, Cheryl H. Arrowsmith, Rima Al-Awar, Rachel J. Harding, Matthieu Schapira
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Correction
Chemistry, Medicinal
David E. Uehling, Babu Joseph, Kim Chan Chung, Andrew X. Zhang, Spencer Ler, Michael A. Prakesch, Gennady Poda, Julie Grouleff, Ahmed Aman, Taira Kiyota, Chungyee Leung-Hagesteijn, John David Konda, Richard Marcellus, Carly Griffin, Ratheesh Subramaniam, Ayome Abibi, Craig A. Strathdee, Methvin B. Isaac, Rima Al-Awar, Rodger E. Tiedemann
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Meeting Abstract
Oncology
S. Labidi, N. Meti, R. Barua, J. J. Riromar, A. R. Hansen, D. M. Jiang, N. Fallah-Rad, S. Sridhar, C. Ferrario, R. Pezo, S. Cheng, A. Sacher, A. Rose
ANNALS OF ONCOLOGY
(2022)
Article
Oncology
Sabine Schmid, Sierra Cheng, Simren Chotai, Miguel Garcia, Luna Zhan, Katrina Hueniken, Karmugi Balaratnam, Khaleeq Khan, Devalben Patel, Benjamin Grant, Roula Raptis, M. Catherine Brown, Wei Xu, Patrick Moriarty, Frances A. Shepherd, Adrian G. Sacher, Natasha B. Leighl, Penelope A. Bradbury, Geoffrey Liu
Summary: The study aimed to understand the current treatment patterns, toxicities, and outcomes among ALK-positive NSCLC patients. The results show that each generation of ALK-TKIs has a role in treatment, and modifications due to toxicity may not impact survival outcomes.
CLINICAL LUNG CANCER
(2022)
Article
Cell Biology
Maarten P. Bebelman, Matthew J. Bovyn, Carlotta M. Mayer, Julien Delpierre, Ronald Naumann, Nuno P. Martins, Alf Honigmann, Yannis Kalaidzidis, Pierre A. Haas, Marino Zerial
Summary: Bebelman and Bovyn et al. demonstrate that apical bulkheads are load-bearing mechanical elements that contribute to the ability of bile canaliculi to withstand elevated luminal pressure. Through their structure and function analysis, they found that apical bulkheads are sealed by tight junction loops, connected by adherens junctions, and contain contractile actomyosin. The study also revealed that apical bulkheads can double the pressure bile canaliculi can hold and protect the bile duct network against elevated pressure.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Ahmed Mamai, Anh M. Chau, Brian J. Wilson, Iain D. Watson, Babu B. Joseph, Pandiaraju R. Subramanian, Monzur M. Morshed, Justin A. Morin, Michael A. Prakesh, Tianbao Lu, Pete Connolly, Douglas A. Kuntz, Neil C. Pomroy, Gennady Poda, Kong Nguyen, Richard Marcellus, Graig Strathdee, Brigitte Theriault, Ratheesh Subramaniam, Mohammed Mohammed, Ayome Abibi, Manuel Chan, Jeffrey Winston, Taira Kiyota, Elijus Undzys, Ahmed Aman, Nigel Austin, Marc Du Jardin, Kathryn Packman, Ulrike Phillippar, Riccardo Attar, James Edwards, Jeff O'Meara, David E. Uehling, Rima Al-awar, Gilbert G. Prive, Methvin B. Isaac
Summary: BCL6, a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma, especially in diffuse large B-cell lymphoma. In order to find new therapeutic interventions for DLBCL patients, we conducted a program to identify BCL6 inhibitors that interfere with co-repressor binding. After optimization, we discovered a highly potent BCL6 inhibitor (OICR12694/JNJ-65234637) with low nanomolar DLBCL cell growth inhibition and excellent oral pharmacokinetic profile. This inhibitor has the potential to be tested in clinical trials for DLBCL and other neoplasms, especially in combination with other therapies.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Cell Biology
Esra Peker, Konstantin Weiss, Jiyao Song, Christine Zarges, Sarah Gerlich, Volker Boehm, Aleksandra Trifunovic, Thomas Langer, Niels H. Gehring, Thomas Becker, Jan Riemer
Summary: Peker et al. discovered a two-step import pathway that allows proteins to be localized to both the matrix and IMS. Weak targeting signals enable proteins to form stabilizing disulfide bonds in the IMS before being imported into the matrix. This pathway enables the monitoring of import activity in both compartments. The study found that NDUFAF8, a factor involved in complex I assembly, follows this two-step import pathway, and its import is regulated by proteases to ensure proper function.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Oncology
Ashley A. A. Adile, David Bakhshinyan, Yujin Suk, David Uehling, Mehakpreet Saini, Ahmed Aman, Jakob Magolan, Minomi K. K. Subapanditha, Dillon McKenna, Chirayu Chokshi, Neil Savage, Michelle M. M. Kameda-Smith, Chitra Venugopal, Sheila K. K. Singh
Summary: CHK1 and PDGFRβ inhibitors have been found to be effective in targeting treatment-refractory metastases in Group 3 MB, providing promising therapeutic options for these aggressive tumors.
JOURNAL OF NEURO-ONCOLOGY
(2023)
Review
Oncology
Joshua C. Rosen, Adrian Sacher, Ming-Sound Tsao
Summary: KRAS(G12C) inhibitors have shown promising results in clinical trials with overall response rates ranging between 32% and 46%, and have been granted FDA approvals as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy.
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
(2023)
Meeting Abstract
Oncology
Sumanta Pal, Ben Tran, John Haanen, Michael Hurwitz, Adrian Sacher, Neeraj Agarwal, Nizar Tannir, Elizabeth Budde, Simon Harrison, Sebastian Klobuch, Sagar Patel, Mary Lee Dequeant, Verena Karsten, Kaitlyn Cohen, Ellen Gurary, Henia Dar, Anna Ma, Anjali Sharma, Samer Srour
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Meeting Abstract
Oncology
Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Juergen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, Qui Tran, Simon Jones, Agnes Ang, Abraham Anderson, Antreas A. Hindoyan, David S. Hong, Bob T. Li
Meeting Abstract
Immunology
Giselle M. Boukhaled, Ramy Gadalla, Heidi J. Elsaesser, Adrian Sacher, Marcus O. Butler, David G. Brooks
JOURNAL OF IMMUNOLOGY
(2022)
Meeting Abstract
Oncology
C. Poletes, S. C. Cheng, L. J. Zhan, J. Lee, D. Patel, P. A. Bradbury, F. A. Shepherd, N. B. Leighl, A. G. Sacher, G. Liu, S. C. Lau
JOURNAL OF THORACIC ONCOLOGY
(2022)
Meeting Abstract
Oncology
J. Rosen, A. Sacher, N. -A. Pham, J. Weiss, Q. Li, T. Koga, S. Tucker, N. Radulovich, A. Koers, M. Niedbala, S. Ross, M. -S. Tsao
JOURNAL OF THORACIC ONCOLOGY
(2022)