1,724,057 research outputs found
Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia
No full textTreatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML
Mandoline galante. Maîtres napolitains au XVIIIe siècle. Calliope, CAL 9274
No full textWeber Edith. Mandoline galante. Maîtres napolitains au XVIIIe siècle. Calliope, CAL 9274. In: Cahiers de sociologie économique et culturelle, n°35, 2001. p. 123
Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth
Full text linkKidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and one of the relatively few whose incidence is increasing. Because of the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2-M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation, which we show occurs in all RCC cell lines tested, makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC. Mol Cancer Ther; 15(9); 2119-29. ©2016 AACR
Linked collectors and determiners for: SPFR - Herbário do Departamento de Biologia da FFCLRP-USP.
No full textNatural history specimen data linked to collectors and determiners held within, "SPFR - Herbário do Departamento de Biologia da FFCLRP-USP". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/7b203230-ba55-4da6-9274-e1d7b1b95987">https://bionomia.net/dataset/7b203230-ba55-4da6-9274-e1d7b1b95987</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/7b203230-ba55-4da6-9274-e1d7b1b95987">https://gbif.org/dataset/7b203230-ba55-4da6-9274-e1d7b1b95987</a>. Formatted as a Frictionless Data package
KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells
No full textTriple negative breast cancer (TNBC) is difficult to treat due to lack of druggable targets. We have found that treatment with the small molecule inhibitor KPT-9274 inhibits growth of TNBC cells and eventually leads to cell death. KPT-9274 is a dual specific inhibitor of PAK4 and Nicotinamide Phosphoribosyltransferase (NAMPT). The PAK4 protein kinase is often highly expressed in TNBC cells and has important roles in cell growth, survival, and migration. Previously we have found that inhibition of PAK4 leads to growth inhibition of TNBC cells both in vitro and in vivo. Likewise, NAMPT has been shown to be dysregulated in cancer due to its role in cell metabolism. In order to understand better how treating cells with KPT-9274 abrogates TNBC cell growth, we carried out an RNA sequencing of TNBC cells treated with KPT-9274. As a result, we identified Rictor as an important target that is inhibited in the KPT-9274 treated cells. Conversely, we found that Rictor is predicted to be activated when PAK4 is overexpressed in cells, which suggests a role for PAK4 in the regulation of Rictor. Rictor is a component of mTORC2, one of the complexes formed by the serine/threonine kinase mTOR. mTOR is important for the control of cell growth and metabolism. Our results suggest a new mechanism by which the KPT-9274 compound may block the growth of breast cancer cells, which is via inhibition of mTORC2 signaling. Consistent with this, sequencing analysis of PAK4 overexpressing cells indicates that PAK4 has a role in activation of the mTOR pathway
G .-F. Haendel. Un enregistrement d'époque, orgue à cylindres du XVIIIème siècle. ERATO 9274
No full textWeber Edith. G .-F. Haendel. Un enregistrement d'époque, orgue à cylindres du XVIIIème siècle. ERATO 9274. In: Cahiers de sociologie économique et culturelle, n°5, 1986. p. 161
Abstract LB-308: KPT-9274 inhibits cellular NAD and synergizes with doxorubicin to treat dogs with lymphoma
No full textAbstract
Nicotinamide adenine dinucleotide (NAD), an essential metabolite and cofactor of several biological processes (e.g. genomic stability), undergoes significant alterations during malignant transformation. In cancer cells, the high metabolic demands of proliferating cells and increased activity of NAD consuming enzymes (i.e. SIRT1 and PARP1) lead to rapid NAD turnover. NAD can be generated de novo from tryptophan or regenerated by nicotinamide phosphoribosyl transferase (NAMPT) or nicotinate phosphoribosyl transferase 1 (NAPRT1) in NAD salvage pathways. However, cancer cells rely mainly on the NAMPT-dependent pathway, making NAD depletion a promising anti-cancer therapy. KPT-9274 is a novel first-in-class orally bioavailable dual inhibitor of p21-activated kinase 4 (PAK4) and NAMPT that demonstrates potent anti-tumor activity in a variety of cancer cell lines. KPT-9274 treatment rapidly depletes cellular NAD levels, leading to ATP loss and cell death. Similarly, hyper activation of PARP1 through DNA damaging agents (e.g. doxorubicin; DOX) can lead to apoptosis. Here we present results from a phase 1 study of KPT-9274 as a single agent and in combination with DOX for the treatment of dogs with solid tumors or lymphomas.
Methods: Dogs with cancer (lymphoma, n=4; sarcoma n=6; mast cell tumor n=2) were enrolled into a prospective phase 1 dose escalation study of KPT-9274 given qod x 3 per week. Plasma samples were used for pharmacokinetics (PK) and tumor biopsies were used to assess pharmacodynamics (PDn; i.e. PAK4, NAMPT and downstream effectors). In an expansion cohort, dogs with lymphoma (n=6) received 4 doses of KPT-9274 at 2 mg/kg prior to administration of a single dose of DOX.
Results: Doses up to 4 mg/kg KPT-9274 were well tolerated with no grade ≥3 toxicities. At 4.5 mg/kg one dog exhibited severe vomiting, diarrhea, collapse, anemia and thrombocytopenia, establishing 4 mg/kg as MTD. The PK of KPT-9274 was dose proportional and in agreement with healthy dogs. PDn markers (NAD levels) in tumors showed target engagement through NAD depletion as well as changes in PAK4 pathway biomarkers using IHC. Four dogs exhibited stable disease during treatment (3 soft tissue sarcomas, 1 mast cell tumor) at doses ranging from 3 - 4.5 mg/kg. Of the 6 dogs with naïve lymphoma that received KPT-9274 and a single dose of DOX, 5 achieved a complete response, one of which lasted for over 3 months. No unexpected toxicities were noted with the combination when compared to those expected from DOX alone.
Conclusions: KPT-9274 exhibits single agent activity in canine spontaneous cancers. Moreover, the combination of KPT-9274 and DOX has substantial biologic activity against canine Non-Hodgkin lymphoma, likely through the activation of NAD consuming enzymes such as PARP1 by DOX. Importantly, the drug combination was safe with no enhanced toxicity over DOX alone. This data could be applied directly to the current trial of KPT-9274 in a Phase 1 clinical trial in patients with advanced solid malignancies or NHL (NCT02702492).
Citation Format: Cheryl London, Megan Brown, Emma Warry, Elizabeth Schuh, William T. Senapedis, Christian Argueta, Trinayan Kashyap, Hua Chang, Joel Ellis, Sharon Shacham, Erkan Baloglu. KPT-9274 inhibits cellular NAD and synergizes with doxorubicin to treat dogs with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-308. doi:10.1158/1538-7445.AM2017-LB-308</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth
No full textAbstractBreast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy.</jats:p
- …
