scholarly journals Development of Cell Lines for use in COVID-19 Drug Development and Research

2021 ◽  
Vol 7 (5) ◽  
pp. 32-35
Author(s):  
London McGill
Keyword(s):  
Drug Development ◽  
Cell Lines

Application of a Validated QSTR Model for Repurposing COX-2 Inhibitor Coumarin Derivatives as Potential Antitumor Agents

2019 ◽  
Vol 19 (13) ◽  
pp. 1121-1128 ◽  
Author(s):  
Gulcin Tugcu ◽  
Hande Sipahi ◽  
Ahmet Aydin
Keyword(s):  
Antitumor Activity ◽  
Drug Development ◽  
Linear Model ◽  
Cell Lines ◽  
Cyclooxygenase 2 ◽  
Large Set ◽  
Coumarin Derivatives ◽  
Antitumor Compounds ◽  
Cyclooxygenase 2 Inhibitors ◽  
Potential Antitumor

Background: The discovery of novel potent molecules for both cancer prevention and treatment has been continuing over the past decade. In recent years, identification of new, potent, and safe anticancer agents through drug repurposing has been regarded as an expeditious alternative to traditional drug development. The cyclooxygenase-2 is known to be over-expressed in several types of human cancer. For this reason cyclooxygenase-2 inhibition may be useful tool for cancer chemotherapy. Objective: The first aim of the study was to develop a validated linear model to predict antitumor activity. Subsequently, applicability of the model for repurposing these cyclooxygenase-2 inhibitors as antitumor compounds to abridge drug development process. Method: We performed a quantitative structure-toxicity relationship (QSTR) study on a set of coumarin derivatives using a large set of molecular descriptors. A linear model predicting growth inhibition on leukemia CCRF cell lines was developed and consequently validated internally and externally. Accordingly, the model was applied on a set of 143 cyclooxygenase-2 inhibitor coumarin derivatives to explore their antitumor activity. Results: The results indicated that the developed QSAR model would be useful for estimating inhibitory activity of coumarin derivatives on leukemia cell lines. Electronegativity was found to be a prominent property of the molecules in describing antitumor activity. The applicability domain of the developed model highlighted the potential antitumor compounds. Conclusion: The promising results revealed that applied integrated in silico approach for repurposing by combining both the biological activity similarity and the molecular similarity via the computational method could be efficiently used to screen potential antitumor compounds among cyclooxygenase-2 inhibitors.

scholarly journals Abstract 1918: InnoPanelTM-a well characterized panel of 1000 cancer cell lines for anticancer drug development

2019 ◽  
Author(s):  
Feng Hao ◽  
Changpeng Liu ◽  
Hao Peng ◽  
Xiaolin Zhou ◽  
Yunhui Fu ◽  
...  
Keyword(s):  
Drug Development ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Drug ◽  
Cancer Cell Lines ◽  
Anticancer Drug Development

scholarly journals Epigenetic Modifier Mutations in the LL-100 Panel

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5271-5271
Author(s):  
Hilmar Quentmeier ◽  
Claudia Pommerenke ◽  
Hans G. Drexler
Keyword(s):  
Amino Acid ◽  
Drug Development ◽  
Cell Line ◽  
Cell Lines ◽  
Human Cell ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
Human Cell Line ◽  
Dominant Negative ◽  
Epigenetic Modifier

Abstract The NCI-60 human cell line panel, developed for use in drug development comprises sixty human cancer cell lines derived from nine different tissues. Only six cell lines of the NCI-60 were derived from blood cancers. Therefore, most forms and subtypes of leukemia and lymphoma are not represented in the NCI-60 panel. To respond to this apparent gap, we suggest the novel LL-100 panel, 100 leukemia and lymphoma cell lines representing the major leukemia/lymphoma entities, for basic research and drug development. Whole exome sequencing and RNA sequencing were performed to identify mutations in 100 cell lines. Here we list the 100 cell lines, ordered by subtype and show mutations in epigenetic modifier genes. We found cell lines with mutations in ASXL1, EZH2, IDH1, TET2 and in DNMT3A. Hitherto, cell line OCI-AML3 was the only human cell line described with a DNMT3A mutation. Twenty-two percent of patients with acute myeloid leukemia contain DNMT3A mutations and the median overall survival with DNMT3A mutations is shorter than without. Most DNMT3A mutations are heterozygous and alter amino acid R882, R882H being the most common DNMT3A mutation in AML. Exogenously mutant murine R878H (equivalent to human R882H) inhibits DNMT3A activity in a dominant negative manner. We describe here that the AML cell line SET-2 carries a heterozygous G to A transition at chr2_25234373 (hg38) which leads to the DNMT3A R882H amino acid substitution. Chip-based methylation analysis revealed that the described DNMT3A targets IRF8, KLF2, HOXA11 and HOXB2 are hypomethylated in cell lines OCI-AML3 (DNMT3A R882C) and in SET-2 (DNMT3A R882H). These data suggest that SET-2 is a novel model cell line for functional analysis of the DNMT3A R882 mutation and a first gain in knowledge through data mining the LL-100 panel. Disclosures No relevant conflicts of interest to declare.

Mannich Bases: Centrality in Cytotoxic Drug Design

2021 ◽  
Vol 18 ◽  
Author(s):  
Neha V. Bhilare ◽  
Vinayak S. Marulkar ◽  
Pramodkumar J. Shirote ◽  
Shailaja A. Dombe ◽  
Vilas J. Pise ◽  
...  
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
Cell Lines ◽  
Mannich Bases ◽  
Cytotoxic Agents ◽  
Structure Activity ◽  
Anti Cancer ◽  
Methods Of Synthesis ◽  
Future Drug ◽  
Clinical Conditions

: Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic and prodrugs classes and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines and promising leads for future drug development have also been discussed. Structure-activity relationships along with the targets on which these cytotoxic Mannich bases act have been included as well.

Preclinical Development of Triptolide Derivative MRx102 as a Therapeutic Agent for Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3271-3271
Author(s):  
John M. Fidler ◽  
Jinhua An ◽  
John H. Musser ◽  
Duncan H. Mak ◽  
Bing Carter ◽  
...  
Keyword(s):  
Drug Development ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Employment Equity ◽  
Toxicology Study ◽  
Leukemia Cell Lines ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract Abstract 3271 Acute Myeloid Leukemia (AML) is the most common form of adult acute leukemia and the second most common childhood leukemia. AML has the lowest survival rate among leukemias, and the frequency is increasing as the population ages. Current therapies are inadequate, and a need exists for better therapeutic agents to treat AML, both as initial treatment for newly diagnosed patients and for those who have failed current therapy and relapsed. Natural products, such as taxol, have shown activities in a variety of disease states, including cancer. Triptolide is a natural product diterpenoid derived from Tripterygium wilfordii Hook f, and has shown anti-cancer activity in a broad range of solid tumors in preclinical models. It induces apoptosis in various leukemic cell lines and primary AML blasts (Carter, B et al, Blood 2006). Derivatives of triptolide with improved pharmacokinetics and bioavailability offer the opportunity to optimize the activity of triptolide for clinical application in AML. MRx102 is a triptolide derivative that is more hydrophobic than triptolide. It has potent in vitro cytotoxic activity with human tumor and leukemia cell lines, an unusual result for triptolide derivatives because they are usually much less active in vitro than the parent compound. Designed as a prodrug, MRx102 exerts cytotoxic activity with human AML cell lines and other human leukemia cell lines without pre-incubation with plasma esterases (IC50 of 51.0 and 37.1 nM with MV4-11 AML cells at 48 and 72 hours, respectively, ∼55% and ∼36% of the activity of triptolide, respectively). MRx102 decreases the viable CD34+ blasts of AML patient samples (a mean of 79.8 ± 8.8% specific apoptosis at 100 nM, n=3), and overcomes the apoptosis protection by co-cultivated stromal cells (with a similar mean of 74.1 ± 8.5%). MRx102 shows dose-dependent anti-tumor activity with the MV4-11 cell line in nude mouse human AML tumor xenografts. After 42 days of MRx102 dosing at 1.35 mg/kg/day i.p., tumor volume was inhibited by 99.7%. Tumors removed from several mice appeared to be Matrigel pellets rather than vascularized tumors, suggesting that many of the tumors were completely eliminated. In studies with the OCI-AML3 human AML cell line xenograft model, the group receiving MRx102 at 1.35 mg/kg/day i.p. showed similar high activity, with mean tumor volume reduced by as much as 99.2% on day 23 compared to the vehicle control group. Tumors of 7 of 10 mice were smaller than the day 0 volumes at the day 28 end of the study. As part of drug development, toxicology testing with MRx102 was initiated with an acute single dose rat toxicology study with no deaths and no adverse signs up to the top dose of 3.0 mg/kg MRx102 in DMSO/PBS administered i.v. The maximum tolerated dose (MTD) is greater than 3 mg/kg of MRx102, and the no observable adverse effect level (NOAEL) is at least 3 mg/kg. A 7-day subacute rat toxicology study of MRx102 showed no deaths and no adverse signs up to the top dose of 1.5 mg/kg/day MRx102 in DMSO/PBS administered daily i.v. for 7 days. The histopatholgy report shows no findings related to administration of the test article. The MRx102 MTD is greater than 1.5 mg/kg/day, and the NOAEL is at least 1.5 mg/kg/day. Previously observed NOAELs for related compounds have been less than 0.1 mg/kg/day. The current studies show potent anti-tumor activity as well as an unusually positive safety profile for MRx102 when compared to triptolide and other triptolide derivatives. Further MRx102 drug development is underway, with the intention of submitting an Investigational New Drug application to the Food and Drug Administration leading to clinical evaluation of MRx102 in AML patients. Updated results on current drug development activities will be presented at the meeting. This work is supported in part by NCI SBIR Contract HHSN261200900061C to MyeloRx LLC. Disclosures: Fidler: MyeloRx LLC: Employment, Equity Ownership, PI for an NCI Contract to MyeloRx LLC, Patents & Royalties. An:MyeloRx LLC: Employment, Equity Ownership, participant in research under an NCI SBIR Contract to MyeloRx LLC. Musser:MyeloRx LLC: Employment, Equity Ownership, Patents & Royalties, participant in research under an NCI SBIR Contract to MyeloRx LLC. Mak:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Carter:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Andreeff:MyeloRx LLC: Consultancy, participant in research under an NCI SBIR Contract to MyeloRx LLC.

scholarly journals Molecular and Phenotypic Characterisation of Paediatric Glioma Cell Lines as Models for Preclinical Drug Development

PLoS ONE ◽  
2009 ◽  
Vol 4 (4) ◽  
pp. e5209 ◽  
Author(s):  
Dorine A. Bax ◽  
Suzanne E. Little ◽  
Nathalie Gaspar ◽  
Lara Perryman ◽  
Lynley Marshall ◽  
...  
Keyword(s):  
Drug Development ◽  
Cell Lines ◽  
Glioma Cell ◽  
Phenotypic Characterisation ◽  
Preclinical Drug Development ◽  
Glioma Cell Lines

scholarly journals Abstract 3116: Developing engineered and primary cancer cell lines for oncology drug development

2018 ◽  
Author(s):  
Feng Hao ◽  
Wenna Zhang ◽  
Hao Peng ◽  
Feng He ◽  
Zhaoshuai Bai ◽  
...  
Keyword(s):  
Drug Development ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Primary Cancer ◽  
Oncology Drug ◽  
Oncology Drug Development
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