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ACS Medicinal Chemistry Letters

Diana Peña-Solórzano, Matthias Scholler, Günther Bernhardt, Armin Buschauer, Burkhard König, Cristian Ochoa-Puentes
ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use...
August 9, 2018: ACS Medicinal Chemistry Letters
Roberta Rocca, Federica Moraca, Giosuè Costa, Carmine Talarico, Francesco Ortuso, Silvia Da Ros, Giulia Nicoletto, Claudia Sissi, Stefano Alcaro, Anna Artese
In the last years, it has been shown that the DNA secondary structure known as G-quadruplex is also involved in the regulation of oncogenes transcription, such as c-myc , c-Kit , KRAS , Bcl-2 , VEGF , and PDGF . DNA G-quadruplexes, formed in the promoter region of these proto-oncogenes, are considered alternative anticancer targets since their stabilization causes a reduction of the related oncoprotein overexpression. In this study, a structure-based virtual screening toward the experimental DNA G-quadruplex structures of c-myc and c-Kit was performed by using Glide for the docking analysis of a commercial library of approximately 693 000 compounds...
August 9, 2018: ACS Medicinal Chemistry Letters
James A Baker, Michael D Altman, Iain J Martin
In early drug discovery, where chiral syntheses may not yet have been elucidated or enantiomeric separation is not feasible, screening of racemates in metabolic stability assays may offer a pragmatic approach. To assess the risk of incorrectly deprioritizing enantiomers due to misclassification of apparent in vitro intrinsic clearance (CLintapp ), we evaluated (1) theoretical simulations; (2) literature on enantiomeric CLintapp differences; (3) historic MSD data; and (4) new data on enantiomers with high eudysmic ratios and low predicted three-dimensional similarity...
August 9, 2018: ACS Medicinal Chemistry Letters
Alexei S Karpov, Tinya Abrams, Suzanna Clark, Ankita Raikar, Joseph A D'Alessio, Michael P Dillon, Thomas G Gesner, Darryl Jones, Marion Lacaud, William Mallet, Piotr Martyniuk, Erik Meredith, Morvarid Mohseni, Cristina M Nieto-Oberhuber, Daniel Palacios, Francesca Perruccio, Grazia Piizzi, Mauro Zurini, Carl Uli Bialucha
Antibody-drug conjugates (ADCs) are a novel modality that allows targeted delivery of potent therapeutic agents to the desired site. Herein we report our discovery of NAMPT inhibitors as a novel nonantimitotic payload for ADCs. The resulting anti-c-Kit conjugates ( ADC-3 and ADC-4 ) demonstrated in vivo efficacy in the c-Kit positive gastrointestinal stromal tumor GIST-T1 xenograft model in a target-dependent manner.
August 9, 2018: ACS Medicinal Chemistry Letters
Simone Cailotto, Emanuele Amadio, Manuela Facchin, Maurizio Selva, Enrico Pontoglio, Flavio Rizzolio, Pietro Riello, Giuseppe Toffoli, Alvise Benedetti, Alvise Perosa
There is the need for reproducible, simple, high-yielding synthetic protocols aimed at obtaining carbon dots (CDs) with controlled fluorescence, photothermal and photochemical behavior, surface properties, biocompatibility, tumor targeting ability, drug absorption biodistribution, and tumor uptake. This Letter describes a systematic study on the effect of glucose, fructose, and ascorbic acid as starting materials for the preparation of highly luminescent CDs, characterized by a blue emission. Their composition and morphology are investigated by titration of OH surface groups, spectroscopic techniques, and high-resolution transmission electron microscopy (HR-TEM), and their toxicity was tested toward HeLa cells...
August 9, 2018: ACS Medicinal Chemistry Letters
Sarah F Giardina, Douglas S Werner, Maneesh Pingle, Kenneth W Foreman, Donald E Bergstrom, Lee D Arnold, Francis Barany
Tryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase is a donut-shaped tetramer with the active sites facing inward forming a central pore. Bivalent ligands spanning two active sites potently inhibit this configuration, but these large compounds have poor drug-like properties. To overcome some of these challenges, we developed self-assembling molecules, called coferons, which deliver a larger compound in two parts. Using a pharmacophoric core and reversibly binding linkers to span two active sites, we have successfully produced three novel homodimeric tryptase inhibitors...
August 9, 2018: ACS Medicinal Chemistry Letters
Suchitra Ravula, Brad M Savall, Nyantsz Wu, Brian Lord, Kevin Coe, Kai Wang, Mark Seierstad, Devin M Swanson, Jeannie Ziff, Minh Nguyen, Perry Leung, Ray Rynberg, David La, Daniel J Pippel, Tatiana Koudriakova, Timothy W Lovenberg, Nicholas I Carruthers, Michael P Maher, Michael K Ameriks
Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus...
August 9, 2018: ACS Medicinal Chemistry Letters
Shawn J Stachel, Richard Berger, Ashley B Nomland, Anthony T Ginnetti, Daniel V Paone, Deping Wang, Vanita Puri, Henry Lange, Jason Drott, Jun Lu, Jacob Marcus, Michael P Dwyer, Sokreine Suon, Jason M Uslaner, Sean M Smith
Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3 , while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography...
August 9, 2018: ACS Medicinal Chemistry Letters
Bernard Barlaam, Elaine Cadogan, Andrew Campbell, Nicola Colclough, Allan Dishington, Stephen Durant, Kristin Goldberg, Lorraine A Hassall, Gareth D Hughes, Philip A MacFaul, Thomas M McGuire, Martin Pass, Anil Patel, Stuart Pearson, Jens Petersen, Kurt G Pike, Graeme Robb, Natalie Stratton, Guohong Xin, Baochang Zhai
We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound 21 , a highly potent ATM inhibitor (ATM cell IC50 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. In vivo , 21 in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone...
August 9, 2018: ACS Medicinal Chemistry Letters
Lucia Wang, Valeria S Guillen, Naina Sharma, Kevin Flessa, Jian Min, Kathryn E Carlson, Weiyi Toy, Sara Braqi, Benita S Katzenellenbogen, John A Katzenellenbogen, Sarat Chandarlapaty, Abhishek Sharma
An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant...
August 9, 2018: ACS Medicinal Chemistry Letters
Rahaman Navaz Gangji, Nehru Viji Sankaranarayanan, James Elste, Rami A Al-Horani, Daniel K Afosah, Rachel Joshi, Vaibhav Tiwari, Umesh R Desai
Although heparan sulfate (HS) has been implicated in facilitating entry of enveloped viruses including herpes simplex virus (HSV), small molecules that effectively compete with this abundant, cell surface macromolecule remain unknown. We reasoned that entry of HSV-1 involving its glycoprotein D (gD) binding to HS could be competitively targeted through small, synthetic, nonsaccharide glycosaminoglycan mimetics (NSGMs). Screening a library of NSGMs identified a small, distinct group that bound gD with affinities of 8-120 nM...
August 9, 2018: ACS Medicinal Chemistry Letters
Lewis R Vidler, Ian A Watson, Brandon J Margolis, David J Cummins, Michael Brunavs
Biochemical assay interference is becoming increasingly recognized as a significant waste of resource in drug discovery, both in industry and academia. A seminal publication from Baell and Holloway raised the awareness of this issue, and they published a set of alerts to identify what they described as PAINS (pan-assay interference compounds). These alerts have been taken up by drug discovery groups, even though the original paper had a somewhat limited data set. Here, we have taken Lilly's far larger internal data set to assess the PAINS alerts on four criteria: promiscuity (over six assay formats including AlphaScreen), compound stability, cytotoxicity, and presence of a high Hill slope as a surrogate for non-1:1 protein-ligand binding...
August 9, 2018: ACS Medicinal Chemistry Letters
Ryan A McClure, Jon D Williams
Chemoproteomics is an invaluable tool to discover protein targets from phenotypic assays and to understand on- and off-target engagement of potential therapeutic compounds. Highlighted in this technology perspective is our view on how improvements in mass spectrometry (MS)-based proteomics technology have dramatically impacted chemoproteomics. Improvements in sample preparation, MS instrumentation, data acquisition, and quantification strategies have enabled medicinal chemists, chemical biologists, and mass spectrometrists to develop new chemoproteomic experiments and improve existing methods...
August 9, 2018: ACS Medicinal Chemistry Letters
Robert B Kargbo
No abstract text is available yet for this article.
August 9, 2018: ACS Medicinal Chemistry Letters
Tobias Grabe, Jonas Lategahn, Daniel Rauh
The first evidence of osimertinib resistance mediated by the epidermal growth factor receptor (EGFR) mutation C797S was reported three years ago. Since then, no major breakthroughs have been achieved to target the clinically relevant mutant variant that impedes covalent bond formation with irreversible EGFR inhibitors. Although several biochemically active compounds have been described, only a few inhibitors that potently act on the cellular level or in vivo have been introduced so far. Herein, we give an overview of current approaches in the field and highlight the challenges that need to be addressed in future research projects to overcome the C797S-mediated drug resistance...
August 9, 2018: ACS Medicinal Chemistry Letters
Rui Zhang, Guoqing Li, Michael Wismer, Petr Vachal, Steven L Colletti, Zhi-Cai Shi
Recent visible-light photoredox catalyzed C(sp3 )-C(sp2 ) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a profiling study of photocatalytic C(sp3 )-C(sp2 ) cross-coupling, both decarboxylative coupling and cross-electrophile coupling, with 18 pharmaceutically relevant aryl halides by using either Kessil lamp or our newly developed integrated photoreactor. Integrated photoreactor accelerates reaction rate and improves reaction success rate...
July 12, 2018: ACS Medicinal Chemistry Letters
Brian P David, Oleksii Dubrovskyi, Thomas E Speltz, Jeremy J Wolff, Jonna Frasor, Laura M Sanchez, Terry W Moore
Matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) imaging mass spectrometry has emerged as a powerful, label-free technique to visualize penetration of small molecules in vivo and in vitro , including in 3D cell culture spheroids; however, some spheroids do not grow sufficiently large to provide enough area for imaging mass spectrometry. Here, we describe an ex vivo method for visualizing unlabeled peptides and small molecules in tumor explants, which can be divided into pieces of desired size, thus circumventing the size limitations of many spheroids...
July 12, 2018: ACS Medicinal Chemistry Letters
Sobhana Babu Boga, Yongqi Deng, Liang Zhu, Yang Nan, Alan B Cooper, Gerald W Shipps, Ronald Doll, Neng-Yang Shih, Hugh Zhu, Robert Sun, Tong Wang, Sunil Paliwal, Hon-Chung Tsui, Xiaolei Gao, Xin Yao, Jagdish Desai, James Wang, Abdul Basit Alhassan, Joseph Kelly, Mehul Patel, Kiran Muppalla, Subrahmanyam Gudipati, Li-Kang Zhang, Alexei Buevich, David Hesk, Donna Carr, Priya Dayananth, Stuart Black, Hong Mei, Kathleen Cox, Bradley Sherborne, Alan W Hruza, Li Xiao, Weihong Jin, Brian Long, Gongjie Liu, Stacey A Taylor, Paul Kirschmeier, William T Windsor, Robert Bishop, Ahmed A Samatar
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5 ) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3( S )-thiomethyl pyrrolidine analog 7 . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic...
July 12, 2018: ACS Medicinal Chemistry Letters
Sean P Brown, Paul Dransfield, Marc Vimolratana, Liusheng Zhu, Jian Luo, Jane Zhang, XianYun Jiao, Vatee Pattaropong, Simon Wong, Run Zhuang, Gayathri Swaminath, Jonathan B Houze, Daniel C-H Lin
GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 ( 2 ), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 ( 2 ) to AM-6226 ( 14 ) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 ( 14 ) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control...
July 12, 2018: ACS Medicinal Chemistry Letters
Jeffrey C Pelletier, Suzie Chen, Haiyan Bian, Raj Shah, Garry R Smith, Jay E Wrobel, Allen B Reitz
We have previously reported a prodrug strategy based on the marketed drug riluzole (2-amino-6-trifluoromethoxybenzothiazole), associated with the benefits of lower patient to patient variability of exposure and potentially once daily oral dosing, as opposed to the large variance and twice daily dosing, which is currently observed with the parent drug. Riluzole is a glutamate modulator that is currently approved by the US FDA to treat amyotrophic lateral sclerosis (ALS). Riluzole also strongly suppresses the growth of melanoma cells that express the type 1 metabotropic glutamate receptor (GRM1, mGluR1)...
July 12, 2018: ACS Medicinal Chemistry Letters
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