- Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer
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A series of novel, highly potent, selective CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized for non-small-cell lung cancer (NSCLC) therapy. Structure-activity relationship analysis based on enzymatic and cellular activities led to the discovery of a promising inhibitor 21e. 21e potently inhibited CDK9 with IC50 value of 11 nM and suppressed the stemness properties of NSCLC effectively. It could decrease the stemness phenotypes of NSCLC cells, including tumor sphere formation, side-population and stemness markers abundance. 21e displayed good selectivity over the CDK family kinases and kinase profiling assay against 381 kinases. In addition, 21e inhibited cell proliferation, colony-formation, and cell cycle progression and induced apoptosis in NSCLC. In H1299 xenograft mouse model, a once-daily dose of compound 21e at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Studies of mechanisms of action indicated that 21e efficiently inhibited CDK9 signaling pathway and stemness both in vitro and in vivo. Collectively, 21e as a novel CDK9 inhibitor with CSCs inhibition properties could be a promising agent for the treatment of NSCLC.
- Wang, Xin,Yu, Chenhua,Wang, Cheng,Ma, Yakun,Wang, Tianqi,Li, Yao,Huang, Zhi,Zhou, Manqian,Sun, Peiqing,Zheng, Jianyu,Yang, Shengyong,Fan, Yan,Xiang, Rong
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supporting information
(2019/08/02)
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- COMPOUNDS USEFUL AS CSF1 MODULATORS
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This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
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Paragraph 00230; 00231; 00232
(2016/04/26)
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- MOLECULES HAVING PESTICIDAL UTILITY, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES, RELATED THERETO
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This disclosure relates to the field of moiecuies having pesticida i utility against pests in Phyla Arthropoda, Moliusca, and hJematoda, processes to produce such moiecuies, intermediates used In such processes, pesticidai compositions containing such molecules, and processes of using such pesticidai compositions against such pests. These pesticidai compositions may be used, for example, as acaricldes, insecticides, miticides, moilusclcides, and nematicides. This document discloses moiecuies having the following formula ("Formula One").
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Page/Page column 407-408
(2016/10/31)
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- PROTEIN KINASE INHIBITORS
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The present invention relates to novel kinase inhibitors. Compounds of this class have been found to be effective inhibitors of protein kinases; including members of PDGFR and VEGFR families.
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Page/Page column 51-52
(2012/10/18)
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- Identification and hit-to-lead optimization of a novel class of CB1 antagonists
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The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced A log P, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.
- Letourneau, Jeffrey J.,Jokiel, Patrick,Olson, John,Riviello, Christopher M.,Ho, Koc-Kan,McAleer, Lihong,Yang, Jingchun,Swanson, Robert N.,Baker, James,Cowley, Phillip,Edwards, Darren,Ward, Nick,Ohlmeyer, Michael H.J.,Webb, Maria L.
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scheme or table
p. 5449 - 5453
(2011/01/03)
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- ARYL GUANIDINE F1F0-ATPASE INHIBITORS AND RELATED METHODS
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The invention provides to a family of aryl guanidine-based F1F0-ATPase inhibitors, e.g., mitochondrial F1F0-ATPase inhibitors, methods for their discovery, and their use as therapeutic agents for treating certai
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Page/Page column 59-60
(2010/04/06)
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- SUBSTITUTED BENZIMIDAZOLE COMPOUNDS
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Disclosed are substituted benzimidazole compounds of formula (I) wherein R1, R2, R3, R4 and Xa are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for treating diseases and pathological conditions involving inflammation, immunological disorders and allergic disorders. Also disclosed are processes for preparing these compounds and the pharmaceutical compositions comprising these compounds.
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Page 157-158
(2008/06/13)
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- 2-CARBOXAMIDE-BENZIMIDAZOLES USEFUL IN THE TREATMENT AND PREVENTION OF ISCHEMIC REPERFUSION INJURY
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The subject invention relates to compounds having the structure: (I) wherein: (a) R1 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy, the alkyl and aryl portions of preferred R1 having from 1 to about 14 carbon atoms; (b) R3 and R4 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, alkyl-aryloxy, alkylthio, amino, and mono- or dialkylaminio, the alkyl portions of preferred R3 and R4 having from 1 to about 8 carbon atoms; except that R3 and R4 are not both hydrogen; (c) each R5 is independently selected from the group consisting of hydrogen, halo, cyano, alkyl, hydroxy, alkoxy, thio, alkylthio, amino, and mono- or dialkylamino, the alkyl portions of preferred R5 having from 1 to about 8 carbon atoms. The subject invention further relates to compositions comprising these compound. The subject compounds are useful for preventing or treating reperfusion injury of a variety of tissues.
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Page/Page column 6
(2008/06/13)
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