scholarly journals Development of an orally bioavailable stress kinase inhibitor with brain exposure that targets the neuroinflammation‐synaptic dysfunction pathophysiology axis

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Daniel Martin Watterson ◽  
Ottavio Arancio ◽  
Manfred Windisch ◽  
Jeffrey Pelletier ◽  
Saktimayee M. Roy
Keyword(s):  
Kinase Inhibitor ◽  
Synaptic Dysfunction ◽  
Brain Exposure ◽  
Stress Kinase ◽  
Orally Bioavailable

Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor

2010 ◽  
Vol 53 (17) ◽  
pp. 6368-6377 ◽  
Author(s):  
Victor J. Cee ◽  
Laurie B. Schenkel ◽  
Brian L. Hodous ◽  
Holly L. Deak ◽  
Hanh N. Nguyen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Orally Bioavailable

A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3044-3044 ◽  
Author(s):  
H. A. Wakelee ◽  
A. A. Adjei ◽  
J. Halsey ◽  
J. L. Lensing ◽  
J. D. Dugay ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Maximum Tolerated Dose ◽  
Molecule Inhibitor ◽  
Elimination Half ◽  
Orally Bioavailable ◽  
Grade 3 ◽  
Selective Kinase Inhibitor ◽  
To Receive

3044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumor cell growth, angiogenesis, and metastasis, including EGFR (erbB1), erbB2, VEGFR2/KDR, and EphB4. Methods: Patients (pts) with ASM were enrolled in successive cohorts to receive XL647 orally as a single dose on day 1 with PK sampling, followed by 5 continuous daily doses starting on day 4 with additional PK sampling. Pts then continued to receive XL647 for 5 consecutive days, followed by a break, with cycles repeating every 14 days. Tumor imaging was conducted at baseline, after the first 3 or 4 cycles, and then after every 4 cycles. Pts were allowed to stay on-study in the absence of unacceptable toxicity until evidence of disease progression. Results: A total of 37 pts have been treated across 9 dose levels to date: 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, and 7.0 mg/kg. One pt at 3.12 mg/kg had a dose limiting toxicity (DLT) of asymptomatic QTc prolongation on electrocardiogram, resulting in expansion of that cohort. The first two pts who received 7.0 mg/kg experienced DLTs of grade 3 diarrhea, requiring dose reduction. Both pts from the 7.0 mg/kg cohort tolerated 4.68 mg/kg well. Expansion of the 4.68 mg/kg cohort to 6 pts occurred without further DLTs and this is considered the maximum tolerated dose (MTD). One serious adverse event, grade 4 pulmonary embolism, was considered possibly related to study treatment in a pt dosed at 0.28 mg/kg. PK analysis indicates that XL647 shows approximately dose-proportional exposure, a mean time to maximal concentration (tmax) of 6–9 hours and an elimination half-life of 50–70 hours. To date, 1 pt (non-small cell lung cancer [NSCLC]) from cohort 1 had a partial response and 7 others (NSCLC [2], chordoma [2], adenoid cystic carcinoma, adrenocortical carcinoma, colorectal) have had prolonged stable disease (>3 months). Conclusions: XL647 has been well tolerated. An MTD of 4.68 mg/kg oral dosing for 5 consecutive days every 14 days has been established. Exploration of additional dosing schedules is ongoing, including continuous daily dosing. [Table: see text]

DYRK3 Encodes an Inhibitor of Erythroid Differentiation and Is Expressed at High Levels in Patients with Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3661-3661
Author(s):  
David P. Steensma ◽  
Julie C. Porcher ◽  
Antony Chadderton ◽  
Kevin Laubscher ◽  
Deb Jaworski ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Erythroid Differentiation ◽  
Murine Models ◽  
Erythroid Progenitors ◽  
Peripheral Blood Mononuclear ◽  
Anemia Of Chronic Disease ◽  
Orally Bioavailable

Abstract Background: Many patients (pts) with anemia due to impaired erythropoiesis fail to respond to currently available erythropoiesis-stimulating agents or do not wish to receive these agents due to safety concerns. For these pts, novel approaches are needed. DYRK3, an evolutionarily conserved member of an emerging family of serine-threonine kinases, is expressed at high levels in erythropoietic progenitors; murine models suggest that DYRK3 selectively inhibits red cell production during stress erythropoiesis. We sought to determine DYRK3 expression in pts with anemia, and whether in vitro inhibition of DYRK3 augments erythropoiesis. Methods: We performed quantitative RT-PCR for DYRK3 and 4 control genes using whole peripheral blood (WPB) from 14 healthy persons, 5 pts with anemia due to multiple myeloma (MM), and 3 pts with anemia of chronic disease (ACD); in addition, peripheral blood mononuclear cells (PBMCs) were assayed in the 3 ACD and 5 MM pts and bone marrow mononuclear cells (BMMCs) in the MM pts. Erythrocyte subpopulations (CD36+, CD71+, and dual CD36+/CD71+) were quantified by flow cytometry. CFU-E growth was measured from PBMCs and BMMCs in the presence of varying concentrations of GSK626616, an orally bioavailable first-generation DYRK3 kinase inhibitor. Results: Normalized expression of DYRK3 in WPB was 7.2 fold higher in MM pts (p=0.0001) and 3.4 fold higher in pts with ACD (p=0.026) compared to healthy controls. DYRK3 expression was proportional to the degree of anemia, and WPB and PBMC expression of DYRK3 in MM pts correlated well with BMMC expression. The level of DYRK3 expression was proportional to the population of marrow CD36+/CD71+ erythroid progenitors, and inversely proportional to the size of the more mature CD36−/CD71+ population, suggesting that high DYRK3 expression is associated with maturation arrest in humans at a stage of erythroid differentiation roughly corresponding to pre-Ter119pos/CD71high inhibition observed in murine models. Although incubation of pt-derived BMMC or PBMC with GSK626616 at concentrations up to 30 μM, either in the presence or absence of physiological concentrations of erythropoietin, did not augment in vitro CFU-E formation, CFU-E growth overall was poor in the pt samples studied. Conclusion: DYRK3 is expressed at high levels in pts with anemia due to neoplasia or inflammation, and elevated DYRK3 expression is associated with decreased numbers of CD36−/CD71+ red cells. Further studies of the effects of DYRK3 antagonists on human erythropoiesis in vitro are necessary, and clinical trials in anemic patients will be required to determine if DYRK3 antagonists can reverse DYRK3-associated inhibition.

scholarly journals Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3547-3549 ◽  
Author(s):  
J. Stone Doggett ◽  
Kayode K. Ojo ◽  
Erkang Fan ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis
Keyword(s):  
Toxoplasma Gondii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Content Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Orally Bioavailable ◽  
Toxoplasma Gondii Infection ◽  
Bumped Kinase Inhibitor

ABSTRACTToxoplasma gondiiis a unicellular parasite that causes severe brain and eye disease. Current drugs forT. gondiiare limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogensT. gondii, cryptosporidia, and plasmodia. A lead anti-ToxoplasmaBKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosisin vivo.

Sign in / Sign up

Export Citation Format

Share Document