2019
DOI: 10.1021/acs.jmedchem.9b01227
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Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors

Abstract: p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors; however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achie… Show more

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Cited by 22 publications
(28 citation statements)
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“…The number of isoform-specific p38 inhibitors has since increased, including VX-702 ( Damjanov et al, 2009 ), MW-108, MW-181 ( Watterson et al, 2013 ), SCIO 469 ( Hideshima et al, 2004 ), and BMS 582949 targeting p38α ( Emami et al, 2015 ) (see Table 2 ). Development of isoform-specific compounds was based on more targeted inhibitor design strategies ( Lee and Kim, 2017 ; Rohm et al, 2019 ). Nevertheless, non-specific effects of pharmacological p38 kinase inhibitors on other kinases or off-target effects, demand more specific targeting of individual p38 kinases.…”
Section: Central Methods To Study P38 Kinasesmentioning
confidence: 99%
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“…The number of isoform-specific p38 inhibitors has since increased, including VX-702 ( Damjanov et al, 2009 ), MW-108, MW-181 ( Watterson et al, 2013 ), SCIO 469 ( Hideshima et al, 2004 ), and BMS 582949 targeting p38α ( Emami et al, 2015 ) (see Table 2 ). Development of isoform-specific compounds was based on more targeted inhibitor design strategies ( Lee and Kim, 2017 ; Rohm et al, 2019 ). Nevertheless, non-specific effects of pharmacological p38 kinase inhibitors on other kinases or off-target effects, demand more specific targeting of individual p38 kinases.…”
Section: Central Methods To Study P38 Kinasesmentioning
confidence: 99%
“…Ro3206145 p38α/β 4-Azaindoles For p38α = 10 µM Dapper et al, 2013 Optic neuropathy (Dapper et al, 2013) VX-702 p38α Pyridinecarboxamide For p38α = 20 nM Damjanov et al, 2009 Rheumatoid arthritis (Damjanov et al, 2009) MW-108, MW-181 p38α Pyridazine-3-amine For p38α = 30 nM Watterson et al, 2013 Neuroprotection against neurotoxic insult (Xing et al, 2015) SCIO 469 p38α Indole-3-acetamidehydrochloride For p38α = 9 nM Hideshima et al, 2004 Monoclonal gammopathies (Roccaro et al, 2008), multiple myeloma (Hideshima et al, 2004) BMS 582949 p38α Triazine-6carboxamide For p38α = 13 nM Emami et al, 2015 Arterial inflammation (Emami et al, 2015) Development of isoform-specific compounds was based on more targeted inhibitor design strategies (Lee and Kim, 2017;Rohm et al, 2019). Nevertheless, non-specific effects of pharmacological p38 kinase inhibitors on other kinases or off-target effects, demand more specific targeting of individual p38 kinases.…”
Section: Mw151 P38αmentioning
confidence: 99%
“…This compound also exhibited a good in vitro efficacy, quantitatively reducing the LPS stimulated TNF-α release in whole blood at highest assay concentration with an IC50 in the nanomolar range. [31] Compound 93 presented remarkable selectivity within the kinome with dual activity for p38α/β, and only a few off-targets were detected, such as KIT, ZAK, DDR1/2, RSK4, and MYLK4. [31] Bartolini et al (2019) investigated two recently developed pyrazolobenzothiazine-based (COXP4 M12 and COXH11) com- pounds, promising p38 MAPK inhibitors.…”
Section: P38 Mapk Inhibitors In Vitro Studiesmentioning
confidence: 98%
“…[31] Compound 93 presented remarkable selectivity within the kinome with dual activity for p38α/β, and only a few off-targets were detected, such as KIT, ZAK, DDR1/2, RSK4, and MYLK4. [31] Bartolini et al (2019) investigated two recently developed pyrazolobenzothiazine-based (COXP4 M12 and COXH11) com- pounds, promising p38 MAPK inhibitors. COXP4 M12 (IC50: 0.457 μM) presented a binding mode correspondent to type I inhibitors.…”
Section: P38 Mapk Inhibitors In Vitro Studiesmentioning
confidence: 98%
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