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ACS Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/27882199/straightforward-glycoengineering-approach-to-site-specific-antibody-pyrrolobenzodiazepine-conjugates
#1
Pamela Thompson, Ebele Ezeadi, Ian Hutchinson, Ryan Fleming, Binyam Bezabeh, Jia Lin, Shenlan Mao, Cui Chen, Luke Masterson, Haihong Zhong, Dorin Toader, Philip Howard, Herren Wu, Changshou Gao, Nazzareno Dimasi
Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882198/design-synthesis-and-cytotoxic-evaluation-of-novel-tubulysin-analogues-as-adc-payloads
#2
Carolyn A Leverett, Sai Chetan K Sukuru, Beth C Vetelino, Sylvia Musto, Kevin Parris, Jayvardhan Pandit, Frank Loganzo, Alison H Varghese, Guoyun Bai, Bin Liu, Dingguo Liu, Sarah Hudson, Venkata Ramana Doppalapudi, Joseph Stock, Christopher J O'Donnell, Chakrapani Subramanyam
The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882197/site-specific-tandem-knoevenagel-condensation-michael-addition-to-generate-antibody-drug-conjugates
#3
Romas A Kudirka, Robyn M Barfield, Jesse M McFarland, Penelope M Drake, Adam Carlson, Stefanie Bañas, Wes Zmolek, Albert W Garofalo, David Rabuka
Expanded ligation techniques are sorely needed to generate unique linkages for the growing field of functionally enhanced proteins. To address this need, we present a unique chemical ligation that involves the double addition of a pyrazolone moiety with an aldehyde-labeled protein. This ligation occurs via a tandem Knoevenagel condensation-Michael addition. A pyrazolone reacts with an aldehyde to generate an enone, which undergoes subsequent attack by a second pyrazolone to generate a bis-pyrazolone species...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882196/linker-immolation-determines-cell-killing-activity-of-disulfide-linked-pyrrolobenzodiazepine-antibody-drug-conjugates
#4
Donglu Zhang, Thomas H Pillow, Yong Ma, Josefa Dela Cruz-Chuh, Katherine R Kozak, Jack D Sadowsky, Gail D Lewis Phillips, Jun Guo, Martine Darwish, Peter Fan, Jingtian Chen, Changrong He, Tao Wang, Hui Yao, Zijin Xu, Jinhua Chen, John Wai, Zhonghua Pei, Cornelis E C A Hop, S Cyrus Khojasteh, Peter S Dragovich
Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts of a molecule (e.g., antibody-drug conjugates). The in vitro linker immolation of β-mercaptoethyl-carbamate disulfides and DNA alkylation properties of associated payloads were investigated to understand the determinant of cell killing potency of anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient immolation and release of a PBD-dimer with strong DNA alkylation properties were observed following disulfide cleavage of methyl- and cyclobutyl-substituted disulfide linkers...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882195/design-and-synthesis-of-tesirine-a-clinical-antibody-drug-conjugate-pyrrolobenzodiazepine-dimer-payload
#5
Arnaud C Tiberghien, Jean-Noel Levy, Luke A Masterson, Neki V Patel, Lauren R Adams, Simon Corbett, David G Williams, John A Hartley, Philip W Howard
Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882194/optimization-of-tubulysin-antibody-drug-conjugates-a-case-study-in-addressing-adc-metabolism
#6
L Nathan Tumey, Carolyn A Leverett, Beth Vetelino, Fengping Li, Brian Rago, Xiaogang Han, Frank Loganzo, Sylvia Musto, Guoyun Bai, Sai Chetan K Sukuru, Edmund I Graziani, Sujiet Puthenveetil, Jeffrey Casavant, Anokha Ratnayake, Kimberly Marquette, Sarah Hudson, Venkata Ramana Doppalapudi, Joseph Stock, Lioudmila Tchistiakova, Andrew J Bessire, Tracey Clark, Judy Lucas, Christine Hosselet, Christopher J O'Donnell, Chakrapani Subramanyam
As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882193/expanding-the-reach-of-antibody-drug-conjugates
#7
EDITORIAL
Ravi V J Chari
Antibody-drug conjugates (ADCs) represent an emerging new paradigm in cancer therapy. The approval of two ADCs has spurred considerable interest in this area of research, and over 55 ADCs are currently in clinical testing. In order to improve the clinical success rate of ADC therapy, all three components of the ADC: the antibody, linker, and payload have to be optimized. While considerable improvements have been made in antibody properties and target selection, medicinal chemistry efforts have lagged behind, and there is a significant need for innovation in linker design and payloads...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882192/next-generation-antibody-drug-conjugates-adcs-for-cancer-therapy
#8
EDITORIAL
Jagath Reddy Junutula, Hans-Peter Gerber
No abstract text is available yet for this article.
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774138/discovery-of-fluorescence-polarization-probe-for-the-elisa-based-antagonist-screening-of-%C3%AE-1-adrenergic-receptors
#9
Zhao Ma, Zhenzhen Liu, Tianyu Jiang, Tianchao Zhang, Huateng Zhang, Lupei Du, Minyong Li
High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for α1-adrenergic receptors (α1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774137/photoinduced-conversion-of-antimelanoma-agent-dabrafenib-to-a-novel-fluorescent-braf-v600e-inhibitor
#10
Boris Pinchuk, Thorsten von Drathen, Viktoria Opel, Christian Peifer
Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAF(V600E) mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAF(V600E/K) mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774136/combined-interactions-with-i1-i2-imidazoline-binding-sites-and-%C3%AE-2-adrenoceptors-to-manage-opioid-addiction
#11
Maria Elena Giusepponi, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura, Laura Mattioli, Alan Hudson, Eleonora Diamanti, Fabio Del Bello, Mario Giannella, Valerio Mammoli, Corinne Dalila Paoletti, Alessandro Piergentili, Maria Pigini, Wilma Quaglia
Tolerance and dependence associated with chronic opioid exposure result from molecular, cellular, and neural network adaptations. Such adaptations concern opioid and nonopioid systems, including α2-adrenoceptors (α2-ARs) and I1- and I2-imidazoline binding sites (IBS). Agmatine, one of the hypothesized endogenous ligands of IBS, targeting several systems including α2-ARs and IBS, proved to be able to regulate opioid-induced analgesia and to attenuate the development of tolerance and dependence. Interested in the complex pharmacological profile of agmatine and considering the nature of its targets, we evaluated two series of imidazolines, rationally designed to simultaneously interact with I1-/I2-IBS or I1-/I2-IBS/α2-ARs...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774135/design-synthesis-and-antitumor-evaluation-of-4-amino-1h-pyrazole-derivatives-as-jaks-inhibitors
#12
Xuewu Liang, Jie Zang, Mengyuan Zhu, Qianwen Gao, Binghe Wang, Wenfang Xu, Yingjie Zhang
Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a-f and 11b are potent JAKs inhibitors. For example, the IC50 values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC50: 0...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774134/discovery-of-8-membered-ring-sulfonamides-as-inhibitors-of-oncogenic-mutant-isocitrate-dehydrogenase-1
#13
Jason M Law, Sebastian C Stark, Ke Liu, Norah E Liang, Mahmud M Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M Stern, Stephen E Johnston, Yan-Ling Zhang, Gavin P Dunn, Alykhan F Shamji, Stuart L Schreiber
Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774133/no-photoreleaser-deoxyadenosine-and-bile-acid-derivative-bioconjugates-as-novel-potential-photochemotherapeutics
#14
Maria Luisa Navacchia, Aurore Fraix, Nicola Chinaglia, Eleonora Gallerani, Daniela Perrone, Venera Cardile, Adriana C E Graziano, Massimo L Capobianco, Salvatore Sortino
This contribution reports the synthesis of some novel bioconjugates with anticancer activity and able to release nitric oxide (NO) under visible light excitation. The 4-nitro-2-(trifluoromethyl)aniline derivative, a suitable NO photodonor, was conjugated with 2'-deoxyadenosine and urso- and cheno-deoxycholic acid derivatives, through a thioalkylic chain or the 4-alkyl-1,2,3-triazole moiety. Photochemical experiments demonstrated the effective release of NO from 2'-deoxyadenosine and ursodeoxycholic acid conjugates under the exclusive control of visible light inputs...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774132/discovery-of-tak-272-a-novel-potent-and-orally-active-renin-inhibitor
#15
Yasuhiro Imaeda, Hidekazu Tokuhara, Yoshiyuki Fukase, Ray Kanagawa, Yumiko Kajimoto, Keiji Kusumoto, Mitsuyo Kondo, Gyorgy Snell, Craig A Behnke, Takanobu Kuroita
The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774131/development-of-a-potent-and-selective-hdac8-inhibitor
#16
Oscar J Ingham, Ronald M Paranal, William B Smith, Randolph A Escobar, Han Yueh, Tracy Snyder, John A Porco, James E Bradner, Aaron B Beeler
A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774130/enhancing-therapeutic-efficacy-of-cisplatin-by-blocking-dna-damage-repair
#17
Yuwei Cong, Liangyan Wang, Zigui Wang, Shasha He, Dongfang Zhou, Xiabin Jing, Yubin Huang
Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774129/concise-sar-exploration-based-on-the-head-to-tail-approach-discovery-of-pi4kiii%C3%AE-inhibitors-bearing-diverse-scaffolds
#18
Satoru Noji, Noriyoshi Seki, Takaki Maeba, Takayuki Sakai, Eiichi Watanabe, Katsuya Maeda, Kyoko Fukushima, Toru Noguchi, Kazuya Ogawa, Yukiyo Toyonaga, Tamotsu Negoro, Hisashi Kawasaki, Makoto Shiozaki
In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774128/discovery-of-ono-7300243-from-a-novel-class-of-lysophosphatidic-acid-receptor-1-antagonists-from-hit-to-lead
#19
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Hiroshi Kohno, Taku Fujimoto, Hiroshi Saga, Shinji Nakade, Hiromu Habashita, Yoshikazu Takaoka, Takuya Seko
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH)...
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27774127/discovery-of-a-series-of-5-11-dihydro-6h-benzo-e-pyrimido-5-4-b-1-4-diazepin-6-ones-as-selective-pi3k-%C3%AE-%C3%AE-inhibitors
#20
Fleur M Ferguson, Jing Ni, Tinghu Zhang, Bethany Tesar, Taebo Sim, Nam Doo Kim, Xianming Deng, Jennifer R Brown, Jean J Zhao, Nathanael S Gray
Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics...
October 13, 2016: ACS Medicinal Chemistry Letters
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