scholarly journals The Small Molecule Inhibitor G6 Significantly Reduces Bone Marrow Fibrosis and the Mutant Burden in a Mouse Model of Jak2-Mediated Myelofibrosis

2012 ◽  
Vol 181 (3) ◽  
pp. 858-865 ◽  
Author(s):  
Annet Kirabo ◽  
Sung O. Park ◽  
Heather L. Wamsley ◽  
Meghanath Gali ◽  
Rebekah Baskin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Bone Marrow Fibrosis ◽  
Molecule Inhibitor ◽  
Marrow Fibrosis

Axl blockade in vitro and in patients with high-risk MDS by the small molecule inhibitor BGB324.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7059-7059 ◽  
Author(s):  
Sonja Loges ◽  
Isabel Ben Batalla ◽  
Michael Heuser ◽  
Nikolas Berenbrok ◽  
Thomas Schroeder ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Loading Dose ◽  
Bone Marrow Stroma ◽  
Healthy Donors ◽  
Molecule Inhibitor ◽  
Marrow Stroma

7059 Background: The interplay with bone marrow stroma plays an important role in the pathobiology of MDS. Gas6 is secreted by mesenchymal bone marrow stroma cells and promotes survival and therapy resistance of AML cells expressing the Axl receptor. We hypothesized that inhibiting Axl by the small molecule inhibitor BGB324 might hold therapeutic potential in MDS. Methods: We investigated the inhibitory effect of BGB324 on primary bone marrow mononucleated cells (BMMNC) and mesenchymal stroma cells (MSC) from MDS patients in comparison to healthy donors. In the ongoing first-in-patient Phase 1a/b trial BGBC003 A standard 3 + 3 dose escalation study was performed to identify the maximum tolerated dose of BGB324 in patients with previously treated high risk MDS or AML. BGB324 was administered as an oral loading dose on days one and two followed by a reduced daily maintenance. Three dose levels were explored 400/100mg, 600/200mg and 900/300mg. Results: We found that BGB324 inhibited BMMNC from low- and high-risk MDS patients with an IC50 of 2.1 µM and 3.8 µM, respectively (n = 5). In comparison, BMNNC from healthy donors were resistant to BGB324 (IC50 9.4 µM, p < 0.05, n = 10). Axl expression was present in MSC isolated from the BM of MDS patients and BGB324 inhibited the proliferation of MSC from low- and high-risk MDS patients (IC50 2.5 µM and 2.7 µM, respectively; n = 7/5).To date, 3 patients with MDS were treated with 400 mg loading dose and 100 mg maintenance dose of BGB324. Therapy has been well-tolerated and the MTD has not yet been reached. The majority of adverse events reported have been Grade 1 and 2. The most common related adverse events are diarrhea and fatigue. One patient with MDS was treated for 80 weeks and experienced a PR. Evidence of target inhibition was demonstrated by almost complete inhibition of Axl phosphorylation accompanied by reduction in phosphoErk and phosphoAkt signalling at day 21 of treatment. Conclusions: BGB324 is well-tolerated and might represent a promising novel treatment approach in MDS. Safety and efficacy of BGB324 will be explored further in clinical trials. Clinical trial information: NCT02488408.

Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor Pifithrin-mu in a mouse model

2015 ◽  
Vol 49 ◽  
pp. e25-e26
Author(s):  
K. Krukowski ◽  
C.H. Nijboer ◽  
X. Huo ◽  
M. Maj ◽  
A. Kavelaars ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Identification of pharmacodynamics readouts through acute dosing of a small molecule inhibitor of tau self‐association in a tauopathy mouse model

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
Dhruv R. Patel ◽  
Chaya Sussman ◽  
Mindy Greco ◽  
Edward H. Cheesman ◽  
Patricia Lopez ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Self Association

Abstract 4874: Small molecule inhibitor of ezrin inhibits metastasis in a transgenic mouse model of osteosarcoma

2012 ◽  
Author(s):  
Jared T. Murdoch ◽  
Sung-Hyeok Hong ◽  
Gulay Bulut ◽  
George W. Kosturko ◽  
Lauren E. Drebing ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Small Molecule ◽  
Transgenic Mouse Model ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

Small Molecule Inhibitor of Neutrophil Elastase Normalizes Myeloid Differentiation and Improves Impaired Cell Survival Triggered by Elastase Mutations In Patients with Severe Congenital Neutropenia and Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 386-386
Author(s):  
Andrew A. Aprikyan ◽  
Vahagn Makaryan ◽  
Maxim Totrov ◽  
Ruben Abagyan ◽  
David C. Dale
Keyword(s):  
Bone Marrow ◽  
Small Molecule ◽  
Neutrophil Elastase ◽  
Myeloid Leukemia ◽  
Small Molecule Inhibitor ◽  
Myeloid Differentiation ◽  
Severe Congenital Neutropenia ◽  
Wild Type ◽  
Congenital Neutropenia ◽  
Molecule Inhibitor

Abstract Abstract 386 Heterozygous mutations in the neutrophil elastase gene ELANE have been identified as the primary cause of severe congenital neutropenia (SCN) associated with recurring severe infections and evolution to acute myeloid leukemia (AML). As of today, more than 50 substitution, truncation, insertion and deletion mutations have been identified. Animal studies based on knock-in or knockout of ELANE in mice failed to produce severe neutropenia phenotype. We and others previously reported that expression of various mutants but not wild type neutrophil elastase (NE) in human but not murine cells triggers accelerated apoptosis. We also reported that expression of mutant NE (del.145-152), identified in SCN patients one of whom evolved to develop MDS/AML, in human promyelocytic tet-off HL60 cells causes both accelerated apoptosis and characteristic block of myeloid differentiation similar to that seen in bone marrow of SCN patients. Examination of the tertiary structure of NE revealed that most of the mutations leave the active site of the mutant protease intact. We identified a small molecule inhibitor of neutrophil elastase, a derivative of L-malic acid (Merck, USA), that blocked the proteolytic activity of NE by approximately 80% and was capable of restoring impaired myeloid differentiation and normalizing production of myeloid cells expressing del145-152 NE mutant. It is important to note that block of proteolytic activity of NE with the NE-SMI had no adverse effect on control human myeloid progenitor cells expressing wild type NE, thus confirming the gain-of-function effect of NE mutants. More than 20% of SCN patients with NE mutations evolve to develop AML. Molecular modeling and analysis of the tertiary structures of NE available through the Protein Database revealed that 16 different mutations identified in AML patients affect predominantly the N95 or N144 glycosylation sites or the binding pocket of the protease suggesting that altered substrate specificity of the mutant enzyme is the cause of accelerated apoptosis and block of myeloid differentiation in SCN/AML. We sought to obtain bone marrow samples from 2 unrelated SCN/AML patients both on G-CSF treatment harboring either C122Y or insPQ94. Bone marrow purified CD34+ and/or CD34-/CD33+ myeloid progenitors from the patients showed basal level of apoptosis in a range of 20–25%, which gradually increased reaching 40–50% apoptosis by 3 days of culture. Importantly, treatment of primary bone marrow-derived cells with NE-SMI substantially reduced accelerated apoptosis to near initial rate with approximately up to 2-fold reduction of apoptosis by 3 days of culture as determined by flow cytometry. Thus, our findings demonstrate that 1) small molecule inhibitor of neutrophil elastase is effective in blocking accelerated apoptosis triggered by three different NE mutations identified in SCN patients evolved to develop MDS/AML and 2) the small molecule inhibitor of NE is a promising therapeutic agent that should be considered for testing in clinical trials in SCN/AML patients. Disclosures: Dale: Amgen: Consultancy, Research Funding; Merck: Patents & Royalties, Research Support.

P2-506: Efficacy and safety of systemic versus intracerebroventricular delivery of a β-secretase (BACE1) small molecule inhibitor in a mouse model of Alzheimer's disease

2011 ◽  
Vol 7 ◽  
pp. S474-S474
Author(s):  
Deepak Thakker ◽  
Sethu Sankaranarayanan ◽  
Marcy Weatherspoon ◽  
Jonathan Harrison ◽  
Maria Pierdomenico ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Efficacy And Safety ◽  
Model Of Alzheimer’S Disease ◽  
Molecule Inhibitor

scholarly journals A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model

2016 ◽  
Vol 39 (6) ◽  
pp. 807-820 ◽  
Author(s):  
Fang Wang ◽  
Jeremy Travins ◽  
Zhizhong Lin ◽  
Yaguang Si ◽  
Yue Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Type Ii ◽  
Molecule Inhibitor

A Small Molecule Inhibitor Targeting CREB and CBP Inhibits Proliferation of AML Cells In Vitro and In Vivo,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3607-3607
Author(s):  
Grace I Aldana-Masangkay ◽  
Bryan Mitton ◽  
Alan K Ikeda ◽  
Kazunari Yamada ◽  
Bingbing Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Small Molecule ◽  
Binding Protein ◽  
Small Molecule Inhibitor ◽  
Pharmacokinetic Analysis ◽  
Serum Drug Concentration ◽  
Molecule Inhibitor

Abstract Abstract 3607 The cAMP Response Element Binding Protein, CREB, is a nuclear transcription factor that is a downstream target of signaling pathways regulating memory, glucose homeostasis, cell proliferation, differentiation, and survival. We previously demonstrated that CREB is overexpressed at both the protein and mRNA levels in leukemia blasts and in leukemia stem cells. AML patients who overexpress CREB in their bone marrow have an increased risk of relapse and decreased event-free survival. To determine whether CREB is sufficient for leukemogenesis, we created a transgenic mouse in which CREB is expressed under the control of a myeloid specific hMRP8 promoter. Bone marrow progenitors from CREB transgenic mice had higher proliferative potential and replating ability. These mice developed myeloproliferative disease after one year but not acute leukemia, suggesting that CREB is not sufficient to induce myeloid transformation. To determine whether CREB is necessary for leukemia cell proliferation, we transduced AML cells with lentiviral CREB shRNA. We observed that downregulation of CREB led to decreased AML cell proliferation and survival in vitro. Furthermore, our results demonstrated that CREB knockdown inhibits the growth of AML cells in vivo without affecting normal hematopoietic stem cell function. Together, these results strongly suggest that CREB acts as a proto-oncogene and is a potential target for AML therapy. CREB is activated through phosphorylation, leading to the recruitment of the histone acetyltransferase, CREB binding protein (CBP) and subsequent target gene expression. XX-650-23 (MW: 288.3) is a small molecule that was identified through in silico screening methods to inhibit the interaction between CREB and CBP. We tested the effects of the drug on various AML cell lines using MTT assays and trypan blue exclusion. The IC50 ranged from 700 nM to 2 μM after 72 hours of drug treatment. However, treatment of normal human bone marrow progenitors cultured in methylcellulose containing XX-650-23 at a concentration of 10 μM had no effect on colony numbers. We also tested the in vivo effects of XX-650-23 using xenograft NOD-SCID IL-2Rgamma null (NSG) mouse models. To assess toxicity, mice were treated with the drug at various concentrations, ranging from 10 to 20 mg/kg, by intraperitoneal injection (IP) once daily for 28 days. We did not observe any weight loss or hematologic, renal, hepatic, or cardiac toxicity in the mice. We also performed pharmacokinetic analysis to determine the half-life and stability of the drug. After 1 hour of treatment, the serum drug concentration was 33 nM. The estimated drug mean residence time was 7.5 hours. Plasma clearance divided by IP absorption fraction was 9.6 L/min/kg. The mice were treated daily with drug (17.5mg/kg IP) or vehicle control once MV4-11 cells reached a tumor size of 300mm3 or at the time cells were injected. Our results demonstrated significant inhibition of tumor growth with treatment of the drug started on the day of injection of cells compared to waiting until the tumor reached 300mm3. Together, these data suggest that a small molecule inhibitor targeting CREB and CBP interaction is a potential avenue for drug development. We are currently studying the mechanisms by which XX-650-23 inhibits AML cell proliferation and analyzing the effects of combining the drug with chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 2949: YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model

2014 ◽  
Author(s):  
Said Rahim ◽  
Sarah Justvig ◽  
Sung-Hyeok Hong ◽  
Perrer Tosso ◽  
Haydar Celik ◽  
...  
Keyword(s):  
Mouse Model ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor
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