RÉSUMÉ
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].
RÉSUMÉ
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
RÉSUMÉ
RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).
RÉSUMÉ
Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (
Sujet(s)
Sondes moléculaires/métabolisme , Pharmacologie/méthodes , Protéines/métabolisme , Technologie pharmaceutique/méthodesRÉSUMÉ
2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
Sujet(s)
Antinéoplasiques/synthèse chimique , Récepteurs ErbB/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/analogues et dérivés , Inhibiteurs de protéines kinases/synthèse chimique , Pyrimidines/synthèse chimique , Antinéoplasiques/pharmacologie , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests de criblage d'agents antitumoraux/méthodes , Humains , Inhibiteurs de protéines kinases/pharmacologie , Pyrimidines/pharmacologieRÉSUMÉ
A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.
Sujet(s)
Diamines/pharmacologie , Récepteurs ErbB/métabolisme , Oxadiazoles/pharmacologie , Pyrimidines/pharmacologie , Récepteur ErbB-2/métabolisme , Lignée cellulaire , Diamines/synthèse chimique , Diamines/métabolisme , Conception de médicament , Récepteurs ErbB/antagonistes et inhibiteurs , Cellules HeLa , Humains , Oxadiazoles/synthèse chimique , Oxadiazoles/métabolisme , Liaison aux protéines , Pyrimidines/synthèse chimique , Pyrimidines/métabolisme , Récepteur ErbB-2/antagonistes et inhibiteurs , Relation structure-activitéRÉSUMÉ
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.
Sujet(s)
Indoles , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Récepteurs à activité tyrosine kinase/antagonistes et inhibiteurs , Animaux , Aurora kinase A , Aurora kinases , Techniques de chimie combinatoire , Conception de médicament , Indoles/synthèse chimique , Indoles/pharmacologie , Souris , Modèles moléculaires , Structure moléculaire , Relation structure-activité , Facteurs de croissance endothéliale vasculaire/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
Sujet(s)
Antinéoplasiques/pharmacologie , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/composition chimique , Oximes/pharmacologie , Pyrimidines/pharmacologie , Récepteur ErbB-2/antagonistes et inhibiteurs , Animaux , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Sites de fixation/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Relation dose-effet des médicaments , Conception de médicament , Tests de criblage d'agents antitumoraux , Humains , Liaison hydrogène , Concentration inhibitrice 50 , Modèles moléculaires , Structure moléculaire , Oximes/synthèse chimique , Oximes/composition chimique , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Rats , Rat Sprague-Dawley , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
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Antinéoplasiques/usage thérapeutique , Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Tumeurs du cerveau/traitement médicamenteux , Antienzymes/usage thérapeutique , Morpholines/composition chimique , Morpholines/usage thérapeutique , Pyrimidines/composition chimique , Pyrimidines/usage thérapeutique , Récepteurs à activité tyrosine kinase/antagonistes et inhibiteurs , Animaux , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Barrière hémato-encéphalique/enzymologie , Tumeurs du cerveau/enzymologie , Lignée cellulaire tumorale , Antienzymes/composition chimique , Antienzymes/pharmacologie , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/métabolisme , Humains , Souris , Souris nude , Souris SCID , Morpholines/pharmacologie , Pyrimidines/pharmacologie , Quinazolines/composition chimique , Quinazolines/pharmacologie , Quinazolines/usage thérapeutique , Récepteurs à activité tyrosine kinase/métabolisme , Récepteur ErbB-2/antagonistes et inhibiteurs , Récepteur ErbB-2/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe/méthodesRÉSUMÉ
A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.
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Néovascularisation cornéenne/traitement médicamenteux , Antienzymes/usage thérapeutique , Pyrimidines/pharmacologie , Récepteur-2 au facteur croissance endothéliale vasculaire/antagonistes et inhibiteurs , Animaux , Néovascularisation cornéenne/anatomopathologie , Modèles animaux de maladie humaine , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Souris , Pyrimidines/synthèse chimique , Relation structure-activitéRÉSUMÉ
The preparation of a novel series of N-aryl CBI derivatives in which an aryl substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue is detailed and its extension to a unique series of N-alkenyl derivatives is reported. The N-aryl derivatives were found to be exceptionally stable and to exhibit well-defined relationships between structure (X-ray), reactivity, and cytotoxic potency. When combined with the results of past investigations, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency. The parabolic relationship establishes that compounds in the series should possess sufficient stability to reach their biological target (DNA), yet maintain sufficient reactivity to effectively alkylate DNA upon reaching the biological target. Just as importantly, it defined this optimal balance of stability and reactivity that may be used for future design of related analogues. Notably, the duocarmycin SA and yatakemycin alkylation subunit lies at this optimal stability/reactivity position, whereas the CC-1065 and duocarmycin A alkylation subunits lie progressively and significantly to the left of this optimal position (too reactive).
Sujet(s)
Agents alcoylants/composition chimique , Agents alcoylants/métabolisme , Séquence nucléotidique/génétique , Cristallographie aux rayons X/méthodes , ADN/génétique , ADN/métabolisme , Évaluation préclinique de médicament/méthodes , Duocarmycines , Indoles/composition chimique , Indoles/métabolisme , Pyrrolidones/composition chimique , Pyrrolidones/métabolismeRÉSUMÉ
The preparation of a novel series of N-aryl CBI derivatives is detailed in which an aryl para substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue (rho = 0.17). The derivatives were found to be exceptionally stable and to exhibit a well-defined relationship between reactivity and cytotoxic potency. When combined with the results of an extensive series of N-acyl CBI analogues and derivatives assembled over the past 15 years, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency.