FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.

• MeSH
• akutní myeloidní leukemie genetika   patologie   MeSH
• antitumorózní látky chemie   metabolismus   farmakologie   MeSH
• diaminy chemie   metabolismus   farmakologie   MeSH
• inhibitory proteinkinas chemie   metabolismus   farmakologie   MeSH
• konformace proteinů MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• objevování léků * MeSH
• simulace molekulového dockingu MeSH
• tyrosinkinasa 3 podobná fms antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An efficient synthetic route for the synthesis of 2H-pyrazolo[4,3-c]pyridines, primarily varying by the substituents at the 2-, 4- and 6-positions, is described here. A Sonogashira-type cross-coupling reaction was employed to yield 3-alkynyl-1H-pyrazole-4-carbaldehydes, ethanones and propanones from the corresponding 1H-pyrazol-3-yl trifluoromethanesulfonates. Subsequent treatment of the coupling products with dry ammonia afforded a versatile library of 2H-pyrazolo[4,3-c]pyridines, which were then evaluated for their cytotoxicity against K562 and MCF-7 cancer cell lines. The most potent of these compounds displayed low micromolar GI50 values in both cell lines. Active compounds induced dose-dependent cell-cycle arrest in mitosis, as shown by flow cytometric analysis of DNA content and phosphorylation of histone H3 at serine-10. Moreover, biochemical assays revealed increased activities of caspases-3/7 in treated cells, specific fragmentation of PARP-1, and phosphorylation of Bcl-2, collectively confirming apoptosis as the mechanism of cell death.

• MeSH
• antimitotika chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• buňky K562 MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mitóza účinky léků   MeSH
• molekulární struktura MeSH
• proliferace buněk účinky léků   MeSH
• pyridiny chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Inhibition of protein kinases is a validated concept for pharmacological intervention in cancers. Many kinase inhibitors have been approved for clinical use, but their practical application is often limited. Here, we describe a collection of 23 novel 2,6,9-trisubstituted purine derivatives with nanomolar inhibitory activities against PDGFRα, a receptor tyrosine kinase often found constitutively activated in various tumours. The compounds demonstrated strong and selective cytotoxicity in the human eosinophilic leukemia cell line EOL-1, whereas several other cell lines were substantially less sensitive. The cytotoxicity in EOL-1, which is known to express the FIP1L1-PDGFRA fusion gene encoding an oncogenic kinase, correlated significantly with PDGFRα inhibition. EOL-1 cells treated with the compounds also exhibited dose-dependent inhibition of PDGFRα autophosphorylation and suppression of its downstream signaling pathways with concomitant G1 phase arrest, confirming the proposed mechanism of action. Our results show that substituted purines can be used as platforms for preparing tyrosine kinase inhibitors with specific activity towards eosinophilic leukemia.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• proliferace buněk účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• růstový faktor odvozený z trombocytů - receptor alfa antagonisté a inhibitory   genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Cell cycle deregulation is a common characteristic of cancer cells. Progression through the cell cycle is controlled by enzymes known as cyclin-dependent kinases (CDKs), whose activity can be upregulated by a wide range of molecular mechanisms. Based on these observations, small molecule CDK inhibitors are being developed as potential cancer therapeutics. Some of these compounds have entered Phase III clinical trials and one of them, palbociclib, recently received accelerated approval from the FDA. However, the complexity of CDK biology and the undesired side effects of the existing inhibitors mean that the hunt for new CDK-targeting drug candidates continues. AREAS COVERED: This article reviews patent applications related to small molecule CDK inhibitors published between 2009 and 2014. EXPERT OPINION: Clinical trials with pan-specific inhibitors have generally yielded unambiguously positive outcomes. However, better results have been achieved with highly specific inhibitors of CDK4/CDK6. This may be due to several factors and has generated considerable interest in the discovery of new mono-specific CDK inhibitors. The development of such compounds is challenging because all CDKs have very similar active sites. Aside from this issue of selectivity, another key challenge is the identification of patients who will benefit from specific therapies.

• MeSH
• antitumorózní látky škodlivé účinky   farmakologie   MeSH
• cílená molekulární terapie MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• inhibitory proteinkinas škodlivé účinky   farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• patenty jako téma MeSH
• racionální návrh léčiv MeSH
• schvalování léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Several inhibitors of cyclin-dependent kinases (CDKs), including the 2,6,9-trisubstituted purine derivative roscovitine, are currently being evaluated in clinical trials as potential anticancer drugs. Here, we describe a new series of roscovitine derivatives that show increased potency in vitro. The series was tested for cytotoxicity against six cancer cell lines and for inhibition of CDKs. For series bearing 2-(hydroxyalkylamino) moiety, cytotoxic potency strongly correlated with anti-CDK2 activity. Importantly, structural changes that increase biochemical and anticancer activities of these compounds also increase elimination half-life. The most potent compounds were investigated further to assess their ability to influence cell cycle progression, p53-regulated transcription and apoptosis. All the observed biological effects were consistent with inhibition of CDKs involved in the regulation of cell cycle and transcription.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buňky K562 MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   metabolismus   MeSH
• HCT116 buňky MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• proliferace buněk účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH