Signalizace B-buněčného receptoru (BCR) se podílí na funkci, proliferaci a přežívání B lymfocytů. Aberantní signalizace BCR, která je typická pro různé B-buněčné malignity, je považována za racionální a poměrně efektivní cíl nízkomolekulárních sloučenin, které již prokázaly svou terapeutickou účinnost v klinických experimentech. Na druhou stranu však jejich použití omezují některé nežádoucí účinky, což nadále stimuluje k vývoji dalších inhibitorů BCR signalosomu. Tento projekt je zaměřen na vývoj nových inhibitorů kinas právě v rámci BCR signalosomu, a to konkrétně na BTK (Bruttonova tyrosinová kinasa), SYK (slezinová tyrosinová kinasa) a PI3K (fosfatidylinositol 3-kinasy). Nedávno se nám podařilo navrhnout a připravit několik imidazo[4,5-b]pyridinů a imidazo[4,5-c]pyridinů, které jako inhibitory kinas nebyly dosud využívány. V rámci tohoto projektu hodláme optimalizovat tyto sloučeniny a objasňovat vztahy mezi strukturou a aktivitou v biochemických a buněčných experimentech.Terapeutická účinnost aktivních derivátů bude případně ověřena v myším modelu vhodného B lymfomu.; The B-cell receptor (BCR) signalling pathway is tightly connected with the function, proliferation and survival of B cells. Aberrant BCR signalling, typical for various B cell malignancies, has been successfully targeted by small molecules kinase inhibitors that have shown an encouraging effect in clinical settings. On the other hand, adverse effects limiting the clinical use of these agents stimulate further discovery and development of drug against the BCR signalosome. This project is focused on development of novel kinase inhibitors of the BCR signalosome members: BTK (Brutton tyrosine kinase), SYK (spleen tyrosine kinase) and PI3K (phosphatidylinositol 3-kinases). We have already designed and prepared several imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines, exploited only rarely as kinase inhibitors. Within this project, the compounds will be further optimized and studied to clarify their structure-activity relationships in biochemical and cellular assays. Therapeutic efficacy of selected lead will be determined in a suitable mouse model of B-cell lymphoma.

• MeSH
• B-buněčný lymfom farmakoterapie   MeSH
• inhibitory fosfoinositid-3-kinasy terapeutické užití   MeSH
• inhibitory tyrosinkinasy antagonisté a inhibitory   MeSH
• kinasa Syk antagonisté a inhibitory   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protinádorové látky terapeutické užití   MeSH
• signální transdukce MeSH
• vyvíjení léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• hodnotící studie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• onkologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.

• MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nehodgkinský lymfom farmakoterapie   MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• pyridiny farmakologie   terapeutické užití   MeSH
• signální transdukce MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.

• MeSH
• agonisté serotoninových receptorů farmakologie   MeSH
• antagonisté serotoninu chemická syntéza   farmakologie   MeSH
• astrocyty účinky léků   MeSH
• imidazoly chemická syntéza   farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• molekulární konformace MeSH
• neurity účinky léků   MeSH
• neuroglie účinky léků   MeSH
• neuroprotektivní látky chemická syntéza   farmakologie   MeSH
• poruchy učení chemicky indukované   prevence a kontrola   MeSH
• potkani Sprague-Dawley MeSH
• pyridiny chemická syntéza   farmakologie   MeSH
• receptory serotoninové účinky léků   MeSH
• receptory spřažené s G-proteiny účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

N-(3-Phenylprop-2-yn-1-yl)-sulfonamides derived from serine and threonine were synthesized using solid-phase synthesis and subjected to reaction with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In contrast to the previously reported formation of 1,4-oxazepanes, this reaction afforded pyrrolidin-3-ones. A mechanistic explanation for this unexpected outcome is proposed, and the limitations and scope of the rearrangement are outlined.

• MeSH
• pyrrolidinony chemická syntéza   MeSH
• serin chemická syntéza   MeSH
• sulfonamidy * chemická syntéza   MeSH
• techniky syntézy na pevné fázi metody   MeSH
• threonin chemická syntéza   MeSH
• trimethylsilylové sloučeniny MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bcr-Abl and Btk kinases are among the targets that have been considered for the treatment of leukemia. Therefore, several strategies have focused on the use of inhibitors as chemotherapeutic tools to treat these types of leukemia, such as imatinib (for Bcr-Abl) or ibrutinib (for Btk). However, the efficacy of these drugs has been reduced due to resistance mechanisms, which have motivated the development of new and more effective compounds. In this study, we designed, synthesized and evaluated 2,6,9-trisubstituted purine derivatives as novel Bcr-Abl and Btk inhibitors. We identified 5c and 5d as potent inhibitors of both kinases (IC50 values of 40 nM and 0.58/0.66 μM for Abl and Btk, respectively). From docking and QSAR analyses, we concluded that fluorination of the arylpiperazine system is detrimental to the activity against two kinases, and we also validated our hypothesis that the substitution on the 6-phenylamino ring is important for the inhibition of both kinases. In addition, our studies indicated that most compounds could suppress the proliferation of leukemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos cells) at low micromolar concentrations in vitro. Finally, we preliminarily demonstrated that 5c inhibited the downstream signaling of both kinases in the respective cell models. Therefore, 5c or 5d possessed potency to be further optimized as anti-leukemia drugs by simultaneously inhibiting the Bcr-Abl and Btk kinases.

• MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   MeSH
• buňky K562 MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• leukemie patologie   prevence a kontrola   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• puriny chemie   farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK) are attractive targets in human haematological malignancies with excessively activated B-cell receptor (BCR) signalling pathways. Entospletinib is a SYK inhibitor that has been evaluated as a clinical candidate. We designed and prepared five isosteres in which the imidazo[1,2-a]pyrazine scaffold of entospletinib was altered to pyrazolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine and purine. The last two isosteres were the most potent SYK inhibitors, with IC50 values in the mid-nanomolar range. Importantly, three compounds also inhibited BTK more effectively than did entospletinib. Further experiments then showed that BCR signalling was suppressed in Ramos cells by the potent compounds. Preliminary kinase inhibition screening also revealed LCK and SRC as additional targets. Our results further support the hypothesis that multikinase targeting compounds could produce more robust responses in the treatment of B lymphoid neoplasms.

• MeSH
• fosforylace MeSH
• indazoly aplikace a dávkování   farmakologie   MeSH
• inhibitory proteinkinas aplikace a dávkování   farmakologie   MeSH
• kinasa Syk antagonisté a inhibitory   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-bcr metabolismus   MeSH
• pyraziny aplikace a dávkování   farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

• MeSH
• apoptóza účinky léků   MeSH
• kontrolní body fáze S buněčného cyklu účinky léků   MeSH
• krystalografie rentgenová MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• lidé MeSH
• molekulární konformace MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A preloaded resin consisting of a thalidomide moiety and an ethylene-oxy linker allows the simple and fast formation of PROTACs. The feasibility of the procedure was illustrated by conjugating different protein kinase inhibitors. The biological functionality of an ibrutinib-like conjugate was then confirmed by a cellular experiment.

• MeSH
• amidy chemická syntéza   MeSH
• inhibitory proteinkinas MeSH
• ligandy MeSH
• močovina chemická syntéza   MeSH
• proteolýza MeSH
• syntetické pryskyřice MeSH
• techniky syntézy na pevné fázi metody   MeSH
• thalidomid * chemická syntéza   MeSH
• triazoly chemická syntéza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6receptor partial inverse agonist in Gssignaling (Ki = 6 nM, IC50 = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT6R-elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest.

• MeSH
• HEK293 buňky MeSH
• imidazoly chemická syntéza   chemie   farmakologie   MeSH
• kognice účinky léků   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• molekulární struktura MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• pyridiny chemická syntéza   chemie   farmakologie   MeSH
• receptory serotoninové metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH