- Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors
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We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.
- Blackledge, Chuck W.,Bonnette, William,Burgess, Joelle,Carson, Jeffrey D.,Creasy, Caretha L.,Elkins, Patricia,Graves, Alan P.,Heerding, Dirk A.,Knapp-Reed, Beth,Kruger, Ryan,Luengo, Juan,McHugh, Charles,Mohammad, Helai,Nagarajan, Raman,Pappalardi, Melissa Baker,Qu, Junya,Reif, Alexander,Schulz, Mark,Stern, Melissa,Su, Dai-Shi,Wang, Liping,Wong, Kristen,Yu, Hongyi,Zeng, Jenny
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supporting information
(2020/02/06)
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- TREATMENT OF FIBROSIS WITH IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are methods of using IRE1 small molecule inhibitors in combination therapies for treating fibrosis in a subject. The IRE1 small molecule inhibitors described herein may be used in combination therapies for treating fibrosis
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Paragraph 00264
(2020/11/30)
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- COMBINATION THERAPIES WITH IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are methods of using IRE1 small molecule inhibitors in combination therapies for treating cancer in a subject. The IRE1 small molecule inhibitors described herein may be used in combination therapies for treating solid and hematologic cancers.
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Paragraph 00288
(2020/12/01)
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- Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer
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A series of novel dipeptidyl boronic acid compounds were designed, synthesized and biologically investigated for the inhibition of the β5 subunit of 20S proteasome and several compounds showed high activities with IC50 values of less than 10 nM. Some of these compounds potently inhibited the multiple myeloma (MM) cancer cell lines with IC50 values of less than 10 nM. It was reported that the inhibition of both β2 and β5 subunits strongly increased the cytotoxicity of proteasome inhibitors in solid tumor cells, so some of the compounds were evaluated for the inhibition of the β2 subunit and the solid tumor triple-negative breast cancer cell line MDA-MB-231. The results showed that three compounds were active for both the β2 subunit and the triple-negative breast cancer cell line MDA-MB-231. The in vivo pharmacokinetic results showed that compound 8t had good biological parameters for both ig and iv administrations. An in vivo pharmacodynamic experiment showed that compound 8t inhibited the β5 subunit in whole blood more greatly than the marketed MLN9708 with the same dose at different time periods. A pathological analysis indicated that the injection of compound 8t in the tumor of a triple-negative breast cancer xenograft mice model led to tumor cell necrosis, nucleus condensation, deep staining, cell fragmentation, dissolution and neutrophil infiltration compared with the control group. The data in hand showed that compound 8t might be an effective candidate for the treatment of both MM and triple-negative breast cancer.
- Lei, Meng,Feng, Huayun,Bai, Enhe,Zhou, Hui,Wang, Jia,Qin, Yanru,Zhang, Haoyang,Wang, Xueyuan,Liu, Zhaogang,Hai, Ou,Liu, Jia,Zhu, Yongqiang
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supporting information
p. 683 - 691
(2019/01/24)
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- Synthesis and application of peptide borate compounds
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The invention belongs to the field of drug synthesis, and specifically relates to a series of novel peptide borate compounds or pharmaceutical salts thereof, and a preparation method and pharmaceutical application thereof. The structure of the peptide borate compounds or the pharmaceutical salts thereof is as shown in a formula I which is described in the specification. The compounds of the invention can be used for preparing proteasome inhibitors, and thus can be further used for treating solid tumors and blood tumors.
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Paragraph 0111-0114
(2019/12/25)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.
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Paragraph 00324
(2019/05/30)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.
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Paragraph 00246
(2019/01/04)
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- 3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies
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Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure-activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage.
- Lei, Meng,Feng, Huayun,Wang, Cheng,Li, Hailing,Shi, Jingmiao,Wang, Jia,Liu, Zhaogang,Chen, Shanshan,Hu, Shihe,Zhu, Yongqiang
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p. 2576 - 2588
(2016/05/10)
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- Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof
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The invention belongs to the field of drug synthesis and in particular relates to a series of novel peptide boric acids as well as an ester compound or pharmaceutical salt thereof, and a preparation method and application of the peptide boric acids as well as the ester compound or pharmaceutical salt thereof in pharmacodynamics. A structure of the peptide boric acid and the ester compound or pharmaceutical salt thereof is shown in a formula I (described in the specification). The compound provided by the invention can be used for preparing a proteasome inhibitor and can further be used for treating solid tumours and blood tumours, wherein the solid tumours are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, nasopharynx cancer and leukemia; and the blood tumours are selected from multiple myeloma, mantle cell lymphoma and histiocytic lymphoma.
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Paragraph 0090; 0091; 0092; 0093
(2016/12/01)
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- Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
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The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
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Page/Page column 182; 183; 184
(2016/09/13)
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- Indium-Catalyzed Amide Allylation of N-Carbonyl Imides: Formation of Azaspiro-γ-lactones via Ring Opening-Reclosure
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A novel and facile synthesis of azaspiro-γ-lactones with a methylene-lactam framework from N-carbonyl imides is described. Mechanistic investigations provide evidence for a two-step reaction process involving ZnCl2-promoted addition of β-amido allylindium species followed by an unexpectedly molecular-sieves-mediated ring opening-reclosure concomitantly with the loss of an N-carbonyl unit.
- Sengoku, Tetsuya,Murata, Yusuke,Aso, Yuwa,Kawakami, Ai,Inuzuka, Toshiyasu,Sakamoto, Masami,Takahashi, Masaki,Yoda, Hidemi
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supporting information
p. 5846 - 5849
(2015/12/11)
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- QUINAZOLINONE COMPOUNDS AND DERIVATIVES THEREOF
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Compounds of Formula I are useful inhibitors of tankyrase. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
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Paragraph 0148-0149
(2014/03/25)
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- HETEROCYCLIC PROTEIN KINASE INHIBITORS
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The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
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Paragraph 00485
(2013/03/26)
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- Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors
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Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
- Hua, Zihao,Bregman, Howard,Buchanan, John L.,Chakka, Nagasree,Guzman-Perez, Angel,Gunaydin, Hakan,Huang, Xin,Gu, Yan,Berry, Virginia,Liu, Jingzhou,Teffera, Yohannes,Huang, Liyue,Egge, Bryan,Emkey, Renee,Mullady, Erin L.,Schneider, Steve,Andrews, Paul S.,Acquaviva, Lisa,Dovey, Jennifer,Mishra, Ankita,Newcomb, John,Saffran, Douglas,Serafino, Randy,Strathdee, Craig A.,Turci, Susan M.,Stanton, Mary,Wilson, Cindy,Dimauro, Erin F.
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p. 10003 - 10015
(2014/01/17)
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- Practical phase-transfer synthesis of N-(ethoxycarbonyl)phthalimide and its analogues
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Potassium imides are N-acylated with ethyl chloroformate in the presence of tetrabutylammonium chloride to form the corresponding N-etyhoxycarbonyl derivatives, useful agents for N-protection of primary amines.
- Siedlecka, Renata,Skarzewski, Jacek
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p. 2081 - 2086
(2007/10/03)
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- A Facile One-pot Synthesis of N-Substituted Phthalimides Using a Catalytic Amount of Crown Ether
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N-Substituted phthalimides, intermediates of the Gabriel synthesis, were obtained in high yields (84-100percent) by the addition of a catalytic amount of 18-crown-6 to the reaction of potassium phthalimide and alkyl halides in toluene.
- Soai, Kenso,Ookawa, Atsuhiro,Kato, Kyoko
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p. 1671 - 1672
(2007/10/02)
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