Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

• Klíčová slova
• AKT, PI3K, PIKK, anticancer therapy, inhibitors,
• MeSH
• 1-fosfatidylinositol-3-kinasa * metabolismus   terapeutické užití   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa * MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• protoonkogenní proteiny c-akt MeSH
• TOR serin-threoninkinasy MeSH

Phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are two related families of kinases that play key roles in regulation of cell proliferation, metabolism, migration, survival, and responses to diverse stresses including DNA damage. To design novel efficient strategies for treatment of cancer and other diseases, these kinases have been extensively studied. Despite their different nature, these two kinase families have related origin and share very similar kinase domains. Therefore, chemical inhibitors of these kinases usually carry analogous structural motifs. The most common feature of these inhibitors is a critical hydrogen bond to morpholine oxygen, initially present in the early nonspecific PI3K and PIKK inhibitor 3 (LY294002), which served as a valuable chemical tool for development of many additional PI3K and PIKK inhibitors. While several PI3K pathway inhibitors have recently shown promising clinical responses, inhibitors of the DNA damage-related PIKKs remain thus far largely in preclinical development.

• MeSH
• 1-fosfatidylinositol-3-kinasa chemie   metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• morfoliny chemie   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• terciární struktura proteinů MeSH
• vodíková vazba MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• morfoliny MeSH
• morpholine MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH

Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer's, Parkinson's and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.

• Klíčová slova
• 14-3-3, ASK1, MAP kinase, kinase, phosphorylation, protein–protein interaction,
• MeSH
• apoptóza fyziologie   MeSH
• fosforylace MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé MeSH
• MAP kinasa-kinasa-kinasa 5 genetika   metabolismus   fyziologie   ultrastruktura   MeSH
• MAP kinasový signální systém MeSH
• MAP kinasy kinas (kinas) genetika   metabolismus   MeSH
• mapy interakcí proteinů genetika   fyziologie   MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• proteiny 14-3-3 metabolismus   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• stres endoplazmatického retikula MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• JNK mitogenem aktivované proteinkinasy MeSH
• MAP kinasa-kinasa-kinasa 5 MeSH
• MAP kinasy kinas (kinas) MeSH
• MAP3K5 protein, human MeSH Prohlížeč
• mitogenem aktivované proteinkinasy p38 MeSH
• proteiny 14-3-3 MeSH
• proteiny regulující apoptózu MeSH

Meiotic oocytes lack classic centrosomes and, therefore, bipolar spindle assembly depends on clustering of acentriolar microtubule-organizing centers (MTOCs) into two poles. However, the molecular mechanism regulating MTOC assembly into two poles is not fully understood. The kinase haspin (also known as GSG2) is required to regulate Aurora kinase C (AURKC) localization at chromosomes during meiosis I. Here, we show that inhibition of haspin perturbed MTOC clustering into two poles and the stability of the clustered MTOCs. Furthermore, we show that AURKC localizes to MTOCs in mouse oocytes. Inhibition of haspin perturbed the localization of AURKC at MTOCs, and overexpression of AURKC rescued the MTOC-clustering defects in haspin-inhibited oocytes. Taken together, our data uncover a role for haspin as a regulator of bipolar spindle assembly by regulating AURKC function at acentriolar MTOCs in oocytes.

• Klíčová slova
• Aurora kinase, Haspin, MTOC, Oocyte, Spindle,
• MeSH
• aparát dělícího vřeténka metabolismus   MeSH
• Aurora kinasa C metabolismus   MeSH
• intracelulární signální peptidy a proteiny antagonisté a inhibitory   metabolismus   MeSH
• metafáze MeSH
• myši MeSH
• oocyty metabolismus   MeSH
• organizační centrum mikrotubulů metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• transport proteinů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Aurora kinasa C MeSH
• Haspin protein, mouse MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• protein-serin-threoninkinasy MeSH

BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca2+/calmodulin-dependent kinase (CaMK) family involved in adiposity regulation, glucose homeostasis and cancer. This upstream activator of CaMKI, CaMKIV and AMP-activated protein kinase is inhibited by phosphorylation, which also triggers an association with the scaffolding protein 14-3-3. However, the role of 14-3-3 in the regulation of CaMKK2 remains unknown. METHODS: The interaction between phosphorylated CaMKK2 and the 14-3-3γ protein, as well as the architecture of their complex, were studied using enzyme activity measurements, small-angle x-ray scattering (SAXS), time-resolved fluorescence spectroscopy and protein crystallography. RESULTS: Our data suggest that the 14-3-3 protein binding does not inhibit the catalytic activity of phosphorylated CaMKK2 but rather slows down its dephosphorylation. Structural analysis indicated that the complex is flexible and that CaMKK2 is located outside the phosphopeptide-binding central channel of the 14-3-3γ dimer. Furthermore, 14-3-3γ appears to interact with and affect the structure of several regions of CaMKK2 outside the 14-3-3 binding motifs. In addition, the structural basis of interactions between 14-3-3 and the 14-3-3 binding motifs of CaMKK2 were elucidated by determining the crystal structures of phosphopeptides containing these motifs bound to 14-3-3. CONCLUSIONS: 14-3-3γ protein directly interacts with the kinase domain of CaMKK2 and the region containing the inhibitory phosphorylation site Thr145 within the N-terminal extension. GENERAL SIGNIFICANCE: Our results suggested that CaMKK isoforms differ in their 14-3-3-mediated regulations and that the interaction between 14-3-3 protein and the N-terminal 14-3-3-binding motif of CaMKK2 might be stabilized by small-molecule compounds.

• Klíčová slova
• 14-3-3 protein, CaMKK, Fluorescence spectroscopy, Protein-protein interaction, SAXS,
• MeSH
• aminokyselinové motivy MeSH
• fosforylace účinky léků   MeSH
• kinasa proteinkinasy závislé na vápníku a kalmodulinu metabolismus   MeSH
• konformace proteinů účinky léků   MeSH
• lidé MeSH
• mapování interakce mezi proteiny MeSH
• molekulární modely MeSH
• posttranslační úpravy proteinů MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 1 metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteinové domény MeSH
• proteiny 14-3-3 metabolismus   MeSH
• rekombinantní proteiny metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CAMK1 protein, human MeSH Prohlížeč
• CAMKK2 protein, human MeSH Prohlížeč
• kinasa proteinkinasy závislé na vápníku a kalmodulinu MeSH
• PRKAA2 protein, human MeSH Prohlížeč
• proteinkinasa závislá na vápníku a kalmodulinu typ 1 MeSH
• proteinkinasy aktivované AMP MeSH
• proteiny 14-3-3 MeSH
• rekombinantní proteiny MeSH

The conserved serine-threonine kinase, Cdc7, plays a crucial role in initiation of DNA replication by facilitating the assembly of an initiation complex. Cdc7 is expressed at a high level and exhibits significant kinase activity not only during S-phase but also during G2/M-phases. A conserved mitotic kinase, Aurora B, is activated during M-phase by association with INCENP, forming the chromosome passenger complex with Borealin and Survivin. We show that Cdc7 phosphorylates and stimulates Aurora B kinase activity in vitro. We identified threonine-236 as a critical phosphorylation site on Aurora B that could be a target of Cdc7 or could be an autophosphorylation site stimulated by Cdc7-mediated phosphorylation elsewhere. We found that threonines at both 232 (that has been identified as an autophosphorylation site) and 236 are essential for the kinase activity of Aurora B. Cdc7 down regulation or inhibition reduced Aurora B activity in vivo and led to retarded M-phase progression. SAC imposed by paclitaxel was dramatically reversed by Cdc7 inhibition, similar to the effect of Aurora B inhibition under the similar situation. Our data show that Cdc7 contributes to M-phase progression and to spindle assembly checkpoint most likely through Aurora B activation.

• MeSH
• aparát dělícího vřeténka metabolismus   MeSH
• Aurora kinasa B metabolismus   MeSH
• buněčné dělení MeSH
• buněčný cyklus MeSH
• centromera metabolismus   MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• hmyz MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mitóza MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• survivin metabolismus   MeSH
• threonin chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AURKB protein, human MeSH Prohlížeč
• Aurkb protein, rat MeSH Prohlížeč
• Aurora kinasa B MeSH
• Birc5 protein, rat MeSH Prohlížeč
• CDC7 protein, human MeSH Prohlížeč
• chromozomální proteiny, nehistonové MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH
• survivin MeSH
• threonin MeSH

INTRODUCTION: Cyclin-dependent kinase 7 (CDK7) is a member of the CDK family of serine/threonine protein kinases and participates in the regulation of the cell cycle and mRNA transcription. CDK7 is emerging as a possible drug target in oncology and six exciting drug candidates have already undergone early evaluation in clinical trials. AREAS COVERED: This review examines CDK7 inhibitors as anticancer drugs reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2018-2022 period. This review provides an overview of available inhibitors, including their chemical structures, biochemical profile and stage of development. EXPERT OPINION: Small-molecule CDK7 inhibitors represent attractive pharmacological modalities for the treatment of various cancer types. Highly potent and selective inhibitors have been discovered and many of them show promising results in several preclinical cancer models. Developed compounds act on the kinase by various mechanisms, including traditional ATP competition, irreversible binding to tractable cysteine 312 outside the active site of CDK7, and induced protein degradation by proteolysis targeting chimeras. Ongoing preclinical research and clinical trials should reveal which strategy will provide the highest benefits.

• Klíčová slova
• CAK, PROTAC, cancer, cyclin-dependent kinase 7, kinase inhibitor,
• MeSH
• cyklin-dependentní kinasy genetika   MeSH
• inhibitory proteinkinas farmakologie   chemie   MeSH
• kinasa aktivující cyklin dependentní kinasy * MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• patenty jako téma MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cyklin-dependentní kinasy MeSH
• inhibitory proteinkinas MeSH
• kinasa aktivující cyklin dependentní kinasy * MeSH
• protein-serin-threoninkinasy MeSH

In this study, butyrolactone I (BL I), a potent and specific inhibitor of cyclin-dependent kinases (cdk), is shown to inhibit germinal vesicle breakdown (GVBD) in pig oocytes. Oocytes treated with 100 microM BL I were arrested in the germinal vesicle (GV)-stage and displayed low activity of cdc2 kinase and MAP kinase. Nevertheless, chromosome condensation occurred and highly condensed bivalents were seen within an intact GV after a 24-hr culture in the presence of BL I. The inhibitory effect of BL I on MAP kinase activation during culture was likely mediated through a cdk-dependent pathway, since MAP kinase activity present in extracts derived from metaphase II eggs was not inhibited by BL I. The block of GVBD could be released by treating oocytes with okadaic acid (OA), an inhibitor of type 1 and 2A phosphatases; 82% of the oocytes treated with the combination of OA/BL I underwent GVBD, and MAP kinase became activated, while cdc2 kinase remained inhibited. These results suggest that both chromosome condensation and GVBD could occur without activation of cdc2 kinase, whereas an increase in MAP kinase activity may be a requisite for GVBD in pig oocytes in conditions when cdc2 kinase activation is blocked by BL I.

• MeSH
• aktivace enzymů účinky léků   MeSH
• chromozomy fyziologie   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• gama-butyrolakton analogy a deriváty   farmakologie   MeSH
• histony metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• kyselina okadaová farmakologie   MeSH
• mitogenem aktivovaná proteinkinasa 1 fyziologie   MeSH
• mitogenem aktivovaná proteinkinasa 3 MeSH
• mitogenem aktivované proteinkinasy fyziologie   MeSH
• oocyty enzymologie   ultrastruktura   MeSH
• prasata genetika   MeSH
• proteinfosfatasy antagonisté a inhibitory   MeSH
• proteinkinasa CDC2 fyziologie   MeSH
• vaječné proteiny antagonisté a inhibitory   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• butyrolactone I MeSH Prohlížeč
• cyklin-dependentní kinasy MeSH
• gama-butyrolakton MeSH
• histony MeSH
• inhibitory enzymů MeSH
• kyselina okadaová MeSH
• mitogenem aktivovaná proteinkinasa 1 MeSH
• mitogenem aktivovaná proteinkinasa 3 MeSH
• mitogenem aktivované proteinkinasy MeSH
• proteinfosfatasy MeSH
• proteinkinasa CDC2 MeSH
• vaječné proteiny MeSH

Two principal kinases, p34cdc2 kinase and MAP kinase play a pivotal role in maturation of mammalian oocytes. In the porcine and bovine oocytes both kinases are activated around the time of germinal vesicle breakdown (GVBD). Butyrolactone I (BL I), a specific inhibitor of cdk kinases, prevents effectively and reversibly resumption of meiosis in the porcine and bovine oocytes. Neither p34cdc2 kinase nor MAP kinase are activated in oocytes inhibited in the GV stage. The bovine oocytes maintained for 48 h in the medium supplemented with BL I, progress subsequently to metaphase II in 91%, their cumuli expand optimally and after in vitro fertilization they possess two pronuclei. When the cdc2 kinase is blocked in the porcine oocytes by BL I, MAP kinase, activated by okadaic acid treatment, is able to substitute cdc2 kinase and induce GVBD. The histone H1 kinase activity sharply decreases in the metaphase II oocytes treated by BL I and one or two female pronuclei are formed. These data indicate that BL I is a useful tool either for the two step in vitro culture of mammalian oocytes or for their activation in nuclear transfer experiments.

• MeSH
• fertilizace in vitro MeSH
• gama-butyrolakton analogy a deriváty   farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• meióza účinky léků   MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• oocyty cytologie   MeSH
• oogeneze fyziologie   MeSH
• prasata MeSH
• proteinkinasa CDC2 metabolismus   MeSH
• savci MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• butyrolactone I MeSH Prohlížeč
• gama-butyrolakton MeSH
• inhibitory enzymů MeSH
• mitogenem aktivované proteinkinasy MeSH
• proteinkinasa CDC2 MeSH

Alopecia areata is a disease of autoimmune origin which causes non scarring hair loss. The extent of alopecia varies from a small patch to complete scalp and body hair loss, which can have huge psychosocial impact for those affected. Treatment modalities which have been used so far included nonspecific immunosuppressive medications, such as corticosteroids, cyclosporine, and methotrexate, or topical immunomodulators, such as diphencyprone, dithranol, and squaric acid dibutylester. The recognition of the importance of Janus kinase pathway in alopecia areata pathogenesis enabled more specific approaches in treatment. Positive outcomes of Janus kinase inhibitors in several trials granted approval for baricitinib which became the first on-label treatment for alopecia areata. The aim of this review is to summarize the role, efficacy and safety of several Janus kinase inhibitors in alopecia areata.

• Klíčová slova
• Alopecia areata, Alopecia areata treatment, Baricitinib, JAK/STAT, Janus kinase inhibitors, Olumiant,
• MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• alopecia areata * farmakoterapie   patologie   MeSH
• inhibitory Janus kinas * terapeutické užití   farmakologie   MeSH
• Janus kinasy terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• inhibitory Janus kinas * MeSH
• Janus kinasy MeSH