Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck

Wityak, John; Das, Jagabandhu; Moquin, Robert V.; Shen, Zhongqi; Lin, James; Chen, Ping; Doweyko, Arthur M.; Pitt, Sidney; Pang, Suhong; Shen, Ding Ren; Fang, Qiong; Fex, H.; Schieven, Gary L.; Kanner, Steven B.; Barrish, Joel C.

doi:10.1016/j.bmcl.2003.08.054

Cited by 48 publications

(32 citation statements)

References 21 publications

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“…Indeed the 2-amino-5-carboxamidothiazoles, dasatinib compound class was originally developed as an inhibitor of the Src-family kinase Lck to inhibit T-cell activation with potential utility as an immunosuppressant (Wityak et al, 2003). Likewise pyrimidopyrimidones such as PD173955 were originally developed as inhibitors of Src kinase (Kraker et al, 2000) and receptor tyrosine kinase inhibitors such a EGFR, FGFR, PDGFR and c-Kit (Panek et al, 1997; Klutchko et al, 1998) and were only later demonstrated to possess potent cellular and enzymatic activity on wild-type and mutant forms of Bcr-Abl (Wisniewski et al, 2002; Dorsey et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl

et al. 2010

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The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I ‘gatekeeper’ mutation. Here we describe a Type-II T315I inhibitor GNF-7, based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, E255V, F317L and M351T in biochemical and cellular assays. In addition, GNF-7 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. GNF-7 is amongst the first type II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design next generation Bcr-Abl kinase inhibitors.

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Section: Resultsmentioning

confidence: 99%

A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl

et al. 2010

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“…The lipophilicity of a compound can be reduced by replacing the isopropyl (clogP ~ 1.5) and phenyl (clogP ~ 2.0) groups with the less lipophilic and isosteric cyclopropyl (clogP ~ 1.2) group. [14][15][16] Similarly, increased metabolic stability is achievable through a) replacing the N-ethyl group, which is susceptible to CYP450-mediated oxidation, with the metabolically stable N-cyclopropyl moiety; 17,18 b) the spirocyclopropanation at the α-C of the glycine amide bond to prevent amide hydrolysis 19 and c) the replacement of the metabolically labile benzylic carbon atom with the spirocyclopropane. 20 Furthermore, locking the E/Z-isomerizable non-cyclic alkene bond into a cyclopropane ring can lead to geometrically stable isomers for in vivo studies.…”

Section: Influence Of the Cyclopropane Ring On Pharmacological Activitymentioning

confidence: 98%

“…104 Therefore, a compound that can potently and selectively inhibit Lck will also inhibit T cell activation and, as a result be of potential use in the treatment of acute and chronic T cell-mediated autoimmune and inflammatory disorders. 105 Wityak and colleagues 16 for the phenyl substituent. Compound 74 also showed excellent selectivity when subjected to in vitro screening against a panel of potential kinase targets.…”

Section: Anti-inflammatory Preclinical/clinical Drug Candidatesmentioning

confidence: 98%

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The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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“…Bisher konnten vier Medikamente der zweiten Generation (Nilotinib (8), [54] Ponatinib (9), [55] Dasatinib (10) [56] und Bosutinib (11) [57] )z ugelassen werden (Abbildung 10).…”

Section: Inhibitoren Der Zweiten Generation Und Resistenzenunclassified

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Agnello¹,

Brand²,

Chellat³

et al. 2019

Angewandte Chemie

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Das natürliche Phänomen der Wirkstoffresistenz stellt eine universelle Beeinträchtigung des Nutzens von pharmazeutischen Wirkstoffen in vielen klinischen Indikationen dar. Antibakterielle und antifungale Wirkstoffe sind dabei ebenso betroffen wie Wirkstoffe zur Behandlung von Krebs, Virusinfektionen oder durch Parasiten hervorgerufene Erkrankungen. Trotz der unterschiedlichen biologischen Zielstrukturen und Organismen, die bei der Entwicklung von Wirkstoffresistenzen involviert sind, konnten grundlegende molekulare Prozesse identifiziert werden, die zum Verständnis des Auftretens von Resistenzen beitragen und die Bekämpfung dieser nachteiligen Mechanismen erlauben. Strukturelle Informationen über die Prinzipien von Wirkstoffresistenzen sind heute vielfältig vorhanden, sodass neue Wirkstoffe entwickelt werden können, die weniger anfällig gegenüber einer Resistenzbildung sein werden. Dieser wissensbasierte Ansatz ist eine Grundlage für den Kampf gegen das unvermeidbare Auftreten von Wirkstoffresistenzen.

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Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck

Cited by 48 publications

References 21 publications

A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl

A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

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