39883-36-8Relevant academic research and scientific papers
Design, synthesis and biological evaluation of arylpyridin-2-yl guanidine derivatives and cyclic mimetics as novel msk1 inhibitors. An application in an asthma model
Bihel, Frédéric,Bollenbach, Maud,Bourguignon, Jean-Jacques,Camelin, Guillaume,Daubeuf, Fran?ois,Frossard, Nelly,Nemska, Simona,Obrecht, Adeline,Rognan, Didier,Schmitt, Martine,Villa, Pascal,Wagner, Patrick
, (2021)
Mitogen-and Stress-Activated Kinase 1 (MSK1) is a nuclear kinase, taking part in the activation pathway of the pro-inflammatory transcription factor NF-kB and is demonstrating a therapeutic target potential in inflammatory diseases such as asthma, psoriasis and atherosclerosis. To date, few MSK1 inhibitors were reported. In order to identify new MSK1 inhibitors, a screening of a library of low molecular weight compounds was performed, and the results highlighted the 6-phenylpyridin-2-yl guanidine (compound 1a, IC50~18 μM) as a starting hit for structure-activity relationship study. Derivatives, homologues and rigid mimetics of 1a were designed, and all synthesized compounds were evaluated for their inhibitory activity towards MSK1. Among them, the non-cytotoxic 2-aminobenzimidazole 49d was the most potent at inhibiting significantly: (i) MSK1 activity, (ii) the release of IL-6 in inflammatory conditions in vitro (IC50~2 μM) and (iii) the inflammatory cell recruitment to the airways in a mouse model of asthma.
Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase
Rosenthal, Andrew S.,Dexheimer, Thomas S.,Gileadi, Opher,Nguyen, Giang H.,Chu, Wai Kit,Hickson, Ian D.,Jadhav, Ajit,Simeonov, Anton,Maloney, David J.
, p. 5660 - 5666 (2013/10/01)
Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome.
