scholarly journals Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 272 ◽  
Author(s):  
Silvia Pietrobono ◽  
Barbara Stecca
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Clinical Settings ◽  
Clinical Use ◽  
Mechanisms Of Resistance ◽  
Tumor Initiating Cells ◽  
Promising Therapeutic Target ◽  
Gli Transcription Factors ◽  
Cancer Types ◽  
Hh Signaling

Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.

Anticancer Immunotoxins, Challenges, and Approaches

2020 ◽  
Vol 26 ◽  
Author(s):  
Maryam Dashtiahangar ◽  
Leila Rahbarnia ◽  
Safar Farajnia ◽  
Arash Salmaninejad ◽  
Arezoo Gowhari Shabgah ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Antibody Fragment ◽  
Clinical Use ◽  
Multiple Cancer ◽  
Main Obstacle ◽  
Cancer Types ◽  
Recombinant Immunotoxins ◽  
Cancerous Cells ◽  
High Immunogenicity ◽  
Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

scholarly journals PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

2021 ◽  
Vol 22 (7) ◽  
pp. 3464
Author(s):  
Rosalin Mishra ◽  
Hima Patel ◽  
Samar Alanazi ◽  
Mary Kate Kilroy ◽  
Joan T. Garrett
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Combination Therapies ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Promising Therapeutic Target ◽  
Cancer Cell Survival ◽  
Current Therapies ◽  
Cancer Types

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

scholarly journals Novel Allosteric Mechanism of P53 Activation by Small Molecules for Targeted Anticancer Therapy

2018 ◽  
Author(s):  
Joanna Zawacka-Pankau ◽  
Vera V. Grinkevich ◽  
Mikhail Burmakin ◽  
Aparna Vema ◽  
Karin Ridderstråle ◽  
...  
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Allosteric Mechanism ◽  
P53 Activation

scholarly journals Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Jennifer H. Kong ◽  
Cullen B. Young ◽  
Ganesh V. Pusapati ◽  
F. Hernán Espinoza ◽  
Chandni B. Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer

2021 ◽  
Vol 22 (18) ◽  
pp. 9953
Author(s):  
Mai Tanaka ◽  
Dietmar W. Siemann
Keyword(s):  
Signaling Pathway ◽  
Receptor Tyrosine Kinase ◽  
Therapeutic Agents ◽  
Therapeutic Interventions ◽  
Therapeutic Resistance ◽  
Clinical Settings ◽  
Affinity Ligand ◽  
Current State ◽  
Cancer Types ◽  
High Affinity Ligand

Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically.

scholarly journals Water-in-Water Emulsion as a New Approach to Produce Mesalamine-Loaded Xylan-Based Microparticles

2019 ◽  
Vol 9 (17) ◽  
pp. 3519
Author(s):  
Bartolomeu S. Souza ◽  
Henrique R. Marcelino ◽  
Francisco Alexandrino ◽  
Silvana C. C. Urtiga ◽  
Karen C. H. Silva ◽  
...  
Keyword(s):  
Small Molecules ◽  
Drug Loading ◽  
Continuous Phase ◽  
Clinical Use ◽  
Water Emulsion ◽  
New Approach ◽  
Emulsion Method ◽  
Discontinuous Phase ◽  
Rapid Diffusion ◽  
Full Factorial

The water-in-water emulsion method has been reported as a technique able to prepare microparticles without using harmful solvents. However, there are few reports showing the encapsulation of small molecules into microparticles produced within this technique. The probable reason relays on the rapid diffusion of these molecules from the discontinuous phase to the continuous phase. In the present study, xylan microparticles containing mesalamine were produced and the doubled crosslinking approach, used to promote higher encapsulation rates, was disclosed. To achieve this goal, a 23 full factorial design was carried out. The results revealed that all formulations presented spherical-shaped microparticles. However, at specific conditions, only few formulations reached up to 50% of drug loading. In addition, the new xylan-based microparticles formulation retained almost 40% of its drug content after 12 h of a dissolution assay likely due to the degree of crosslinking. Thus, the doubled crosslinking approach used was effective on the encapsulation of mesalamine and may pave the way to successfully produce other polysaccharide-based carriers for clinical use.

scholarly journals Biomarkers for Predicting Response to Immunotherapy with Immune Checkpoint Inhibitors in Cancer Patients

2019 ◽  
Vol 65 (10) ◽  
pp. 1228-1238 ◽  
Author(s):  
Michael J Duffy ◽  
John Crown
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Future Research ◽  
Specific Gene ◽  
Tumor Type ◽  
Clinical Use ◽  
Durable Response ◽  
Cancer Types

Abstract BACKGROUND Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary. CONTENT Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8+ lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers. SUMMARY Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.

A balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer

2020 ◽  
Vol 49 (19) ◽  
pp. 6995-7014 ◽  
Author(s):  
Jessica J. Miller ◽  
Christian Gaiddon ◽  
Tim Storr
Keyword(s):  
Small Molecules ◽  
Therapeutic Intervention ◽  
P53 Protein ◽  
P53 Pathway ◽  
Cancer Types

Small molecules targeting various aspects of the p53 protein pathway have shown significant promise in the treatment of a number of cancer types.

Antifungals

2016 ◽  
Author(s):  
M. Estée Török ◽  
Fiona J. Cooke ◽  
Ed Moran
Keyword(s):  
Mechanism Of Action ◽  
Mode Of Action ◽  
Antifungal Agents ◽  
Clinical Use ◽  
Mechanisms Of Resistance ◽  
Action Mechanisms

This chapter provides a systematic summary of antifungal agents, grouped by class and mechanism of action. Each summary provides information on the mode of action, mechanisms of resistance, pharmacology, and clinical use.

scholarly journals Hedgehog Signaling Pathway and Autophagy in Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2279 ◽  
Author(s):  
Xian Zeng ◽  
Dianwen Ju
Keyword(s):  
Drug Resistance ◽  
Hedgehog Signaling ◽  
Biological Process ◽  
Cellular Component ◽  
Hedgehog Signaling Pathway ◽  
Drug Resistant ◽  
Multiple Cancers ◽  
Success Stories ◽  
Cancer Types ◽  
Hh Signaling

Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.

Sign in / Sign up

Export Citation Format

Share Document