ChemInform Abstract: Chemical ′Jekyll and Hyde′s: Small-Molecule Inhibitors of Developmental Signaling Pathways

ChemInform ◽  
2011 ◽  
Vol 42 (45) ◽  
pp. no-no
Author(s):  
Tomoya Sakata ◽  
James K. Chen
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Developmental Signaling

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 Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways

2015 ◽  
Vol 11 (6) ◽  
pp. 909-918 ◽  
Author(s):  
Danysh Abetov ◽  
Zhanar Mustapova ◽  
Timur Saliev ◽  
Denis Bulanin ◽  
Kanat Batyrbekov ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cell Signaling Pathways

scholarly journals Small Molecule Inhibitors of the Candida albicans Budded-to-Hyphal Transition Act through Multiple Signaling Pathways

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e25395 ◽  
Author(s):  
John Midkiff ◽  
Nathan Borochoff-Porte ◽  
Dylan White ◽  
Douglas I. Johnson
Keyword(s):  
Candida Albicans ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Multiple Signaling

Effects of Small-Molecule Inhibitors of TNFR2 Signaling Pathways On TNF-Mediated Expansion of CD4+FoxP3+ Regulatory T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4722-4722
Author(s):  
Xueqiang Wu ◽  
Yan Chen ◽  
Chunsheng Han ◽  
Yiwen Gong ◽  
Dingfang Bu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Conflicts Of Interest ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
P38 Mapk Inhibitor

Abstract Abstract 4722 TNF is a pleiotropic cytokine with biphasic proinflammatory and immunosuppressive effects. Previous work clearly demonstrated that TNF has the capacity to preferentially activate and promote the proliferative expansion of CD4+FoxP3+ regulatory T cells (Tregs), which represent a basis for the paradoxical anti-inflammatory action of TNF. Our studies also indicate that TNFR2, one of the TNF receptor which is preferentially expressed by Tregs, mediates the Treg-activating effect of TNF. However, the molecular mechanism and signaling pathways mediated Treg-activating effect of TNF remain to be understood. In this study, we first further verified that TNFR2 transduces the activating signal of TNF on Tregs, based on the evidence that 1) human TNF, known to only bind to mouse TNFR1, did not activate mouse Tregs; 2) a blocking anti mouse TNFR2 Ab, but not TNFR1 Ab, dose-dependently inhibited TNF-mediated proliferation of mouse Tregs at concentrations of 2.5–500 ng/ml. We next examined the signaling pathways of TNFR2 leading to the proliferation of Tregs, by using specific small-molecule inhibitors. It is well established that the activation of IKK-NFkB is a major consequence of activation of TNFR2. However, small molecule inhibitors of NFkB signaling pathway, namely BAY11–7082 and Sulfasalazine, did not block TNF-mediated proliferation of Tregs. In contrast, small molecule inhibitors of MAPK signaling pathway, SB203580 (P38 MAPK inhibitor), SP600125 (JNK inhibitor) and PD98059 (Erk1/2 inhibitor), potently suppressed TNF-induced replication of Tregs in a dose-dependent manner. Our results indicate that TNF selectively stimulates the expansion of FoxP3+ Tregs through TNFR2. Activation of MAPK (ERK1/2,P38 and JNK), rather than NFkB, is responsible for this activity of TNF. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document