Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety

Arai, Tadamasa; Ohno, M.; Inoue, Hideki; Hayashi, Sotaro; Aoki, Toyohiro; Hirokawa, Hiroe; Meguro, Hiroyuki; Koga, Yoko; Oshida, Keiyu; Kainoh, Mie; Suyama, Kazuharu; Kawai, Hideki

doi:10.1016/j.bmcl.2012.05.095

Cited by 13 publications

(11 citation statements)

References 19 publications

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“…BIRB-796 has a reported IC 50 for p38 in the low-nanomolar range, and yet, to achieve demonstrable cell-based activity, it is necessary to use higher concentrations. 35 At higher concentrations, our own data as well as others indicate that BIRB-796 reduces the phosphorylation, thus activation, of p38 in addition to reducing its enzymatic activity, indicating that it may be inhibiting other upstream kinases in the MAPK cascade. 25,35 We have also observed a similar phenomenon with a different ATP-competitive p38 inhibitor, SB203580 (data not shown).…”

Section: Discussionsupporting

confidence: 56%

“…35 At higher concentrations, our own data as well as others indicate that BIRB-796 reduces the phosphorylation, thus activation, of p38 in addition to reducing its enzymatic activity, indicating that it may be inhibiting other upstream kinases in the MAPK cascade. 25,35 We have also observed a similar phenomenon with a different ATP-competitive p38 inhibitor, SB203580 (data not shown). Compound 1, on the other hand, is able to exert a demonstrable reduction in p38 activity in cells without reducing the level of p38 phosphorylation or the phosphorylation state of related kinases JNK and ERK.…”

Section: Discussionsupporting

confidence: 56%

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Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

et al. 2016

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Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders and has been implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials, with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all adenosine triphosphate (ATP)-competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened ~32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound that is both non-ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non-ATP-competitive p38 inhibitor that is active in cells and, as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit non-ATPcompetitive inhibitors of p38 activity.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 56%

Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

et al. 2016

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“…To this end, selective inhibitors of ERK1/2, p38 and JNK were employed. As shown in Figure 4B , pretreatment with U0126, a highly selective inhibitor of MEK1/2 (upstream kinases of ERK1/2), or doramapimod (also named BIRB 796), a highly selective p38α MAPK inhibitor [ 30 ], markedly suppressed CPX-induced phosphorylation of ERK1/2 or p38, respectively. However, neither of the inhibitors apparently affected CPX-induced LC3-II expression, suggesting that ERK1/2 and p38 MAPK are not involved in CPX-induced autophagy.…”

Section: Resultsmentioning

confidence: 99%

Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway

et al. 2014

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Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells. It appeared that CPX-induced autophagy was attributed to induction of reactive oxygen species (ROS), as N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, prevented this process. Furthermore, we observed that CPX induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK, which was also blocked by NAC. However, only inhibition of JNK (with SP600125) or expression of dominant negative c-Jun partially prevented CPX-induced autophagy, indicating that ROS-mediated activation of JNK signaling pathway contributed to CPX-induced autophagy. Of interest, inhibition of autophagy by chloroquine (CQ) enhanced CPX-induced cell death, indicating that CPX-induced autophagy plays a pro-survival role in human rhabdomyosarcoma cells. Our finding suggests that the combination with autophagy inhibitors may be a novel strategy in potentiating the anticancer activity of CPX for treatment of rhabdomyosarcoma.

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“…Both ATP-competitive and non-competitive molecules have been identified such as VX-745 (neflamapimod), MW150 and the related MW181, PH-797804, BMS-582949, PF-03715455 and an allosteric binder. Notably, multiple structures have been generated with both ATP-and non-ATP site binders, often through an attempt to improve on selectivity profiles (Fitzgerald et al, 2003;Swahn et al, 2005;Sack et al, 2008;Scior et al, 2011;Arai et al, 2012;Getlik et al, 2012;Astolfi et al, 2019) and reviewed in Astolfi et al (2018).…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Benn¹,

Dawson

2020

Front. Aging Neurosci.

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Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.

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Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety

Cited by 13 publications

References 19 publications

Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

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