Review
Pharmacology & Pharmacy
Yazan Haddad, Marek Remes, Vojtech Adam, Zbynek Heger
Summary: The study utilized variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. These families shared similar mutational profiles, ligand R-groups facing the C-helix, mutation sites, and DFG domain.
DRUG DISCOVERY TODAY
(2021)
Article
Chemistry, Medicinal
Meredith S. Eno, Jason D. Brubaker, John E. Campbell, Chris De Savi, Timothy J. Guzi, Brett D. Williams, Douglas Wilson, Kevin Wilson, Natasja Brooijmans, Joseph Kim, Aysegul Ozen, Emanuele Perola, John Hsieh, Victoria Brown, Kristina Fetalvero, Andrew Garner, Zhuo Zhang, Faith Stevison, Rich Woessner, Jatinder Singh, Yoav Timsit, Caitlin Kinkema, Clare Medendorp, Christopher Lee, Faris Albayya, Alena Zalutskaya, Stefanie Schalm, Thomas A. Dineen
Summary: While EGFR tyrosine kinase inhibitors have revolutionized the treatment of NSCLC, the development of resistance mutations remains a challenge. This study introduces a novel reversible inhibitor, BLU-945, that shows promising activity against different resistance mutations. Clinical trials are currently underway to evaluate its efficacy and safety.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Geunho Choi, Daegeun Kim, Junehwan Oh
Summary: This study utilized artificial intelligence to discover potential drugs that can overcome acquired resistance in lung cancer patients, reducing the limitations of the current drug discovery process.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Medicine, Research & Experimental
Hui Hua, Jiajia Zeng, Haixin Xing, Yuxin He, Linyu Han, Nasha Zhang, Ming Yang
Summary: This study systematically evaluated the role of genetic variants in A-to-I editing genes on the prognosis of NSCLC patients receiving EGFR-TKIs therapy. The researchers identified several SNPs in the ADAR gene that were significantly associated with patient prognosis and found that silencing ADAR enhanced the sensitivity of NSCLC cells to gefitinib. These findings highlight the importance of A-to-I RNA editing in drug resistance and suggest ADAR as a potential therapeutic target for unresectable NSCLC.
Article
Chemistry, Medicinal
Tiancheng Fu, Yingying Zuo, Zhenpeng Zhong, Xuan Chen, Zhengying Pan
Summary: In this study, a novel series of selective and irreversible inhibitors of BLK were discovered, showing potent antiproliferative activities against several B-cell lymphoma cell lines. These compounds represent the first selective inhibitors developed for BLK, which could expedite the exploration of BLK functions.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Celine Greco, Anne-Charlotte Ponsen, Stephanie Leclerc-Mercier, Joel Schlatter, Salvatore Cisternino, Claude Boucheix, Christine Bodemer
Summary: This study investigated the possibility of using erlotinib and lapatinib to treat painful palmoplantar keratoderma in patients with pachyonychia congenita. The results showed that oral erlotinib at a dose of 75 mg/day could alleviate pain and reduce hyperkeratosis to some extent. Oral lapatinib, while reducing pain and improving symptoms, also had side effects. The effectiveness of erlotinib cream was inconclusive. Oral Her1 or 1/2 inhibitors offer promising therapeutic perspectives for patients with pachyonychia congenita.
Review
Chemistry, Medicinal
Adileh Ayati, Setareh Moghimi, Mahsa Toolabi, Alireza Foroumadi
Summary: Despite advancements in cancer treatment, EGFR inhibitors have shown significant improvement in targeted therapy. However, the emergence of epigenetic mutation and resistance issues have limited their effectiveness, leading to the need for further research in this field. Recent studies have focused on genetic alterations in the EGFR tyrosine kinase domain, resulting in the development of more selective and effective inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Hematology
Alexey V. Danilov, Daniel O. Persky
Summary: Advancements in understanding the disease progression of haematological malignancies have led to the development of novel targeted therapies, such as acalabrutinib, which show promise in improving treatment outcomes for patients with CLL/SLL and MCL. With its high selectivity and potential to reduce off-target toxicity, it has gained accelerated approval for clinical use and has demonstrated efficacy in phase 3 trials.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Cell Biology
Elisabete Cruz Da Silva, Laurence Choulier, Jessica Thevenard-Devy, Christophe Schneider, Philippe Carl, Philippe Ronde, Stephane Dedieu, Maxime Lehmann
Summary: EGFR, a therapeutic target in GBM, is closely regulated by endocytosis proteins, indicating a potential therapeutic target for improving GBM treatment.
Review
Oncology
Daisy Wai-Ka Chan, Horace Cheuk-Wai Choi, Victor Ho-Fun Lee
Summary: This study conducted a systematic review and meta-analysis to investigate the treatment-related adverse events (trAEs) of combined epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) in advanced non-small cell lung cancer (NSCLC). The results demonstrated a higher incidence of grade >= 3 trAEs in combination TKI and ICI, particularly in skin, gastrointestinal tract, and interstitial lung diseases. However, the interpretation of these results should be cautious due to the limited number of studies included in this meta-analysis.
Article
Chemistry, Medicinal
Yasheng Zhu, Xiuquan Ye, Hao Shen, Jiaxing Li, Zeyu Cai, Wenjian Min, Yi Hou, Haojie Dong, Yuxing Wu, Liping Wang, Xiao Wang, Yibei Xiao, Peng Yang
Summary: In this study, a novel EGFR inhibitor targeting Osimertinib resistance was identified by virtual screening and compound synthesis. The representative compound showed potent antitumor activity and good pharmacokinetic properties and oral bioavailability.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Hyoung-oh Jeong, Hayoon Lee, Hyemin Kim, Jinho Jang, Seunghoon Kim, Taejoo Hwang, David Whee-Young Choi, Hong Sook Kim, Naeun Lee, Yoo Mi Lee, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Semin Lee, Se-Hoon Lee
Summary: The study found that specific cell types such as lung epithelial precursor cells and transitional effector T cells, as well as an immunosuppressive microenvironment, were enriched in the MPE of EGFR TKI-resistant patients, potentially associated with their response to TKI therapy.
Article
Medicine, Research & Experimental
Dan Yan, Justus M. Huelse, Dmitri Kireev, Zikang Tan, Luxiao Chen, Subir Goyal, Xiaodong Wang, Stephen Frye, Madhusmita Behera, Frank Schneider, Suresh S. Ramalingam, Taofeek Owonikoko, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Summary: Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI). Activation of MERTK is associated with OSI resistance and inhibition of MERTK kinase can resensitize resistant cells to OSI.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Biochemistry & Molecular Biology
Milena Casula, Marina Pisano, Panagiotis Paliogiannis, Maria Colombino, Maria Cristina Sini, Angelo Zinellu, Davide Santeufemia, Antonella Manca, Stefania Casula, Silvia Tore, Renato Lobrano, Antonio Cossu, Giuseppe Palmieri
Summary: Oncogenic mutations in the EGFR gene are targets of tyrosine kinase inhibitors in lung adenocarcinoma patients. Liquid biopsy of ctDNA is increasingly used to detect EGFR mutations. This study compared three different techniques and found that real-time PCR-based methods showed equivalent detection ability to the NGS assay for circulating EGFR mutations, but the NGS assay had a poor ability to detect T790M.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, Research & Experimental
Pengxing He, Jing Jing, Linna Du, Xuyang Zhang, Yufei Ren, Han Yang, Bin Yu, Hongmin Liu
Summary: YS-363 is a novel EGFR inhibitor that demonstrates potent reversible inhibition and excellent activities against cell proliferation, migration, cell cycle and apoptosis. It is a promising selective inhibitor that can potentially be developed as a more effective anti-lung cancer agent targeting EGFR.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Chemistry, Medicinal
Dirk Kessler, Moriz Mayer, Stephan K. Zahn, Markus Zeeb, Simon Woehrle, Andreas Bergner, Jens Bruchhaus, Tuncay Ciftci, Georg Dahmann, Maike Dettling, Sandra Doebel, Julian E. Fuchs, Leonhard Geist, Wolfgang Hela, Christiane Kofink, Roland Kousek, Franziska Moser, Teresa Puchner, Klaus Rumpel, Maximilian Scharnweber, Patrick Werni, Bernhard Wolkerstorfer, Dennis Breitsprecher, Philipp Baaske, Mark Pearson, Darryl B. McConnell, Jark Boettcher
Summary: Aberrant activation of the WNT pathway leads to nuclear accumulation of beta-catenin, a key oncogenic event. Mutations in the APC gene impair proteasomal degradation of beta-catenin and promote its nuclear translocation. Fragment-based discovery of a small molecule binder to beta-catenin, along with elucidation of the binding mode, was achieved through X-ray crystallography.
Article
Chemistry, Applied
Joyce C. Leung, Thach T. Nguyen, Mariusz Krawiec, Donghong A. Gao, Jonathan T. Reeves
Summary: A scalable and practical process for preparing trans-4-fluorocyclohexylamine hydrochloride (1a) is described, utilizing the gem-difluoride motif in commercially available 4,4-difluorocyclohexanecarboxylic acid to selectively access the trans-configuration of 1a.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Medicinal
Darryl B. McConnell
Summary: At the core of drug design lies the importance of discovering molecules that can bind tightly to their targets. Biotin is a prime example of achieving high affinity binding with a small molecular weight through the use of flexible side chains and various nonclassical hydrogen bonds. The lessons and advantages from biotin's approach should be more widely adopted in the field of drug design.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Ulrike Tontsch-Grunt, Paula-Elena Traexler, Anke Baum, Hanny Musa, Kristell Marzin, Shaonan Wang, Francesca Trapani, Harald Engelhardt, Flavio Solca
Summary: This study highlights the potential of the novel BET inhibitor, BI 894999, as a combination drug. The authors propose a new clinical scheduling regimen and show that rational combination studies with CCS1477 lead to tumor regression in NUT carcinoma xenograft models.
BRITISH JOURNAL OF CANCER
(2022)
Editorial Material
Biotechnology & Applied Microbiology
Andreas Gollner, Markus Koester, Paul Nicklin, Thomas Trieselmann, Elliott Klein, Jaromir Vlach, Claudia Heine, Marc Grundl, Juergen Ramharter, David Wyatt, Menorca Chaturvedi, Alessio Ciulli, Katharine C. Carter, Susanne Mueller, Daniel Bischoff, Peter Ettmayer, Eric Haaksma, Juergen Mack, Darryl McConnell, Dirk Stenkamp, Harald Weinstabl, Matthias Zentgraf, Clive R. Wood, Florian Montel
Summary: Pharmacological probes are essential for studying disease biology and developing new therapies. The Boehringer Ingelheim open innovation portal opnMe.com addresses the issue of using inadequate molecules by sharing extensively validated probes with the scientific community.
NATURE REVIEWS DRUG DISCOVERY
(2022)
Article
Chemistry, Applied
Nicole Wamser, Hao Wu, Frederic Buono, Anthony Brundage, Francesco Ricci, Jon C. Lorenz, Jun Wang, Nizar Haddad, Joshua Paolillo, Joyce C. Leung, Heewon Lee, Azad Hossain
Summary: Sterically hindered chiral ketones play an important role in the synthesis of active pharmaceutical ingredients. A scalable and highly enantioselective synthesis process using a wild-type ketoreductase (KRED) enzyme has been reported. The process was thoroughly investigated with DoE optimizations and a kinetic study. Scaling up the reaction revealed enzyme aggregation/deactivation challenges, which were overcome to obtain the desired enantiomer in high yields and enantiomeric excesses with relatively low enzyme loadings (2-4 wt %).
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Chemistry, Organic
Yongda Zhang, Eugene Chong, Jada A. H. White, Suttipol Radomkit, Yibo Xu, Stephanie C. Kosnik, Jon C. Lorenz
Summary: An improved chemical process for the synthesis of (S,S)-DACH-Ph Trost ligand has been developed. The process is simple and high-yielding, and purification can be achieved without the need for column chromatography.
Article
Chemistry, Physical
Alexander Steiner, Johannes Krieger, Reinaldo Jones, Dietrich Boese, Yanping Wang, Hans-Michael Eggenweiler, Jason D. Williams, C. Oliver Kappe
Summary: In this study, a batch and a flow photoredox methodologies were developed for the synthesis of PROTACs molecules, enabling the cross-electrophile coupling of alkyl bromides with E3 ligase-binding aryl bromides. The optimized conditions facilitated stable reactions in an oscillatory flow photochemical reactor, allowing for higher yields and shorter reaction times.
Article
Chemistry, Medicinal
Joachim Broeker, Alex G. Waterson, Chris Smethurst, Dirk Kessler, Jark Boettcher, Moriz Mayer, Gerhard Gmaschitz, Jason Phan, Andrew Little, Jason R. Abbott, Qi Sun, Michael Gmachl, Dorothea Rudolph, Heribert Arnhof, Klaus Rumpel, Fabio Savarese, Thomas Gerstberger, Nikolai Mischerikow, Matthias Treu, Lorenz Herdeis, Tobias Wunberg, Andreas Gollner, Harald Weinstabl, Andreas Mantoulidis, Oliver Kraemer, Darryl B. McConnell, Stephen W. Fesik
Summary: Activating mutations in KRAS, especially KRASG12C located at position 12, are common in cancer. Most of the discovered KRASG12C inhibitors covalently bind to the cysteine at this position. However, this study presents a different approach, in which reversible binding small molecules were identified and optimized for non-covalent binding to the switch II pocket. The newly discovered KRASG12C inhibitor, BI-0474, shows in vivo activity and opens up possibilities for the discovery of inhibitors against other oncogenic KRAS mutants.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Boettcher, Alberto Vides, Carlos I. I. Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y. Xue, Andreas Mantoulidis, Joachim Broeker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa de Stanchina, Ben Sang, Chuanchuan Li, Darryl B. B. McConnell, Norbert Kraut, Piro Lito
Summary: This study reports the discovery of a non-covalent inhibitor that selectively binds to the inactive state of KRAS while sparing other RAS isoforms. The inhibitor blocks nucleotide exchange and inhibits the activation of wild-type and various KRAS mutants. It shows promising therapeutic potential for KRAS-driven cancers.
Article
Chemistry, Organic
Ivan Volchkov, Brent V. Powell, Olga V. Zatolochnaya, Joyce C. Leung, Scott Pennino, Lifen Wu, Nina C. Gonnella, Bangaru Bhaskararao, Marisa C. Kozlowski, Jonathan T. Reeves
Summary: This article reports a practical method for the synthesis of di- and trisubstituted vinyl fluorides through a selective olefination/hydrolysis reaction. The method allows for the production of the desired compounds with high isomeric purity and without the need for tedious chromatography.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Applied
Yongda Zhang, Jada A. H. White, Eugene Chong, Suttipol Radomkit, Yibo Xu, Jing Liu, Jon C. Lorenz
Summary: Asymmetric allylic alkylation (AAA) is a powerful and efficient tool for synthesizing a variety of chiral compounds with high yields and enantioselectivity. A highly practical and economical AAA process is desired for the large-scale production of ethyl (R)-1-allyl-2-oxocyclohexane-1-carboxylate 1. By optimizing reaction parameters such as temperature, concentration, stoichiometric amount of TMG, and water, a greatly improved reaction protocol was developed using 0.025 mol% of [η(3)-C3H5PdCl]2 as the catalyst.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Oncology
Birgit Wilding, Dirk Scharn, Dietrich Boese, Anke Baum, Valeria Santoro, Paolo Chetta, Renate Schnitzer, Dana A. Botesteanu, Christoph Reiser, Stefan Kornigg, Petr Knesl, Alexandra Hoermann, Anna Koeferle, Maja Corcokovic, Simone Lieb, Guido Scholz, Jens Bruchhaus, Markus Spina, Josef Balla, Biljana Peric-Simov, Jasmin Zimmer, Sophie Mitzner, Thomas N. Fett, Alexandra Beran, Lyne Lamarre, Thomas Gerstberger, Daniel Gerlach, Markus Bauer, Andreas Bergner, Andreas Schlattl, Gerd Bader, Matthias Treu, Harald Engelhardt, Stephan Zahn, Julian E. Fuchs, Johannes Zuber, Peter Ettmayer, Mark Pearson, Mark Petronczki, Norbert Kraut, Darryl B. McConnell, Flavio Solca, Ralph A. Neumuller
Summary: The study identifies potent inhibitors that selectively target HER2 exon 20 insertion mutations, providing a potential treatment option for non-small cell lung cancer.