Clinical Trials of Small Molecule Inhibitors in High-Grade Glioma

2012 ◽  
Vol 23 (3) ◽  
pp. 407-416 ◽  
Author(s):  
Samuel E. Day ◽  
Allen Waziri
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
High Grade Glioma ◽  
High Grade

Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed

2019 ◽  
Vol 20 (11) ◽  
pp. 1091-1111 ◽  
Author(s):  
Maryam Zanjirband ◽  
Soheila Rahgozar
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tp53 Gene ◽  
Therapeutic Agents ◽  
Negative Regulator ◽  
Mdm2 Protein ◽  
Independent Effects ◽  
Small Hydrophobic ◽  
Targeted Therapeutic

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

scholarly journals Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

2020 ◽  
Vol 21 (20) ◽  
pp. 7549
Author(s):  
Paula Martín Moyano ◽  
Václav Němec ◽  
Kamil Paruch
Keyword(s):  
Clinical Trials ◽  
Protein Kinases ◽  
Small Molecule ◽  
Chemical Biology ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Chemical Probes ◽  
The Family

Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.

scholarly journals 3552 Advancing Glioblastoma (GBM) drug regimen development to support combination therapy through integrated PKPD modeling and simulation-based predictions

2019 ◽  
Vol 3 (s1) ◽  
pp. 1-2
Author(s):  
Saugat Adhikari ◽  
Harlan E. Shannon ◽  
Karen E. Pollok ◽  
Robert E. Stratford
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Tumor Volume ◽  
Small Molecule Inhibitors ◽  
Combination Drug ◽  
Resistance Development ◽  
Pkpd Model

OBJECTIVES/SPECIFIC AIMS: Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma remains fatal; the median survival rate is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, metastasis and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ), creates a substantial clinical challenge.The primary focus of our work is to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, our aim is to combine TMZ with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. METHODS/STUDY POPULATION: To accomplish this objective, an integrated PKPD modeling approach is used. The approach is largely based on the work of Cardilin, et al, 2018. A PK model for each drug is first defined. This is subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models are tumor static concentration (TSC) curves of dual or triple combination drug regimens that identify combination drug exposures predicted to arrest tumor growth. This approach has been applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib efficacy in combination with TMZ in a glioblastoma xenograft model (Raub, et al, 2015). RESULTS/ANTICIPATED RESULTS: A PKPD model was developed to predict tumor growth kinetics for TMZ and abemaciclib monotherapy, as well as combination therapy. Population PK models in immune deficient NSG mice for temozolomide and abemaciclib were developed based on data obtained from original and published studies. Subsequently, the PK model was linked to tumor volume data obtained from U87-MG GBM subcutaneous xenografts, again using both original data as well as data from the Raub, et al, 2015 study. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 30%). The developed PKPD model was used to calculate plasma concentrations of TMZ and abemaciclib that would arrest tumor growth, as well as combinations of concentrations of the two drugs that would accomplish the same endpoint. This so-called TSC curve for the TMZ and abemaciclib combination pair evidenced an additive effect of the two agents when administered together. These results will be presented. In addition, results from on-going PKPD studies of TMZ in combination with two other small molecule inhibitors, RG7388, an MDM2 inhibitor, and GDC0068, an AKT inhibitor, will also be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: Our long-term goals are to further elucidate SOC-induced responses in GBM and establish combination treatment regimens that are safe and significantly improve therapeutic efficacy. Collectively, our studies will broadly influence chemotherapy of GBM by establishing a process to rationally design combination approaches that mitigate resistance development. These studies will ultimately provide opportunities to study other targeted agents tailored to individual molecular signatures of GBM, as well as other tumor types.

scholarly journals ATIM-09. SUCCESSFUL EXPERIENCE WITH CLINICAL TRIALS FOR HIGH GRADE GLIOMA IN A COMMUNITY SETTING

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi19-vi19
Author(s):  
Lars Anker ◽  
Lavinia Dobrea ◽  
Joy Nakhla ◽  
Viorela Pop ◽  
Lawrence Wagman
Keyword(s):  
Clinical Trials ◽  
Community Setting ◽  
High Grade Glioma ◽  
High Grade

Identification of Inhibitors against Botulinum Neurotoxins: 8-Hydroxyquinolines Hold Promise

2019 ◽  
Vol 19 (20) ◽  
pp. 1694-1706
Author(s):  
Ritika Chauhan ◽  
Vinita Chauhan ◽  
Priyanka Sonkar ◽  
Ram Kumar Dhaked
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Biological Warfare ◽  
Potential Drug ◽  
Diverse Range ◽  
Biological Warfare Agents ◽  
Warfare Agents ◽  
Botulinum Neurotoxins ◽  
Privileged Structures

Botulinum neurotoxins (BoNTs) are the most toxic category A biological warfare agents. There is no therapeutics available for BoNT intoxication yet, necessitating the development of a medical countermeasure against these neurotoxins. The discovery of small molecule-based drugs has revolutionized in the last two decades resulting in the identification of several small molecule inhibitors of BoNTs. However, none progressed to clinical trials. 8-Hydroxyquinolines scaffold-based molecules are important ‘privileged structures’ that can be exploited as inhibitors of a diverse range of targets. In this review, our study of recent reports suggests the development of 8-hydroxyquinoline derived molecules as a potential drug may be on the horizon.

Structure-based Drug Design Strategies in the Development of Small Molecule Inhibitors Targeting Bcl-2 Family Proteins

2020 ◽  
Vol 17 (8) ◽  
pp. 943-953
Author(s):  
Zhe Yin ◽  
Donglin Yang ◽  
Jun Wang ◽  
Yuequan Jiang
Keyword(s):  
Clinical Trials ◽  
Drug Design ◽  
B Cell ◽  
Cancer Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Design Strategies ◽  
Structure Based Drug Design

Proteins of B-cell lymphoma (Bcl-2) family are key regulators of apoptosis and are involved in the pathogenesis of various cancers. Disrupting the interactions between the antiapoptotic and proapoptotic Bcl-2 members is an attractive strategy to reactivate the apoptosis of cancer cells. Structure-based drug design (SBDD) has been successfully applied to the discovery of small molecule inhibitors targeting Bcl-2 proteins in past decades. Up to now, many Bcl-2 inhibitors with different paralogue selectivity profiles have been developed and some were used in clinical trials. This review focused on the recent applications of SBDD strategies in the development of small molecule inhibitors targeting Bcl-2 family proteins.

Assessment of efficacy of dendritic cell therapy and viral therapy in high grade glioma clinical trials. A meta-analytic review

2018 ◽  
Vol 40 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Bogdan Ionel Vatu ◽  
Stefan-Alexandru Artene ◽  
Adeline-Georgiana Staicu ◽  
Adina Turcu-Stiolica ◽  
Catalin Folcuti ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dendritic Cell ◽  
Cell Therapy ◽  
High Grade Glioma ◽  
High Grade ◽  
Viral Therapy ◽  
Analytic Review ◽  
Dendritic Cell Therapy

scholarly journals Comparative effect of immunotherapy and standard therapy in patients with high grade glioma: a meta-analysis of published clinical trials

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Stefan-Alexandru Artene ◽  
Adina Turcu-Stiolica ◽  
Marius Eugen Ciurea ◽  
Catalin Folcuti ◽  
Ligia Gabriela Tataranu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Standard Therapy ◽  
Meta Analysis ◽  
High Grade Glioma ◽  
High Grade ◽  
Comparative Effect
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