New developments in small molecules targeting p53 pathways in anticancer therapy

2008 ◽  
Vol 69 (6) ◽  
pp. 289-296 ◽  
Author(s):  
Chit Fang Cheok ◽  
David P. Lane
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
New Developments

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 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.

scholarly journals A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

2021 ◽  
Vol 22 (5) ◽  
pp. 2769
Author(s):  
Joonseong Hur ◽  
Jaebong Jang ◽  
Jaehoon Sim
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Small Molecules ◽  
Biologically Active ◽  
Synthetic Methods ◽  
Pharmacological Activities ◽  
New Developments ◽  
The Past ◽  
Privileged Structures ◽  
Significant Attention

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.

scholarly journals Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4392
Author(s):  
Simone Pellegrino ◽  
Salvatore Terrosu ◽  
Gulnara Yusupova ◽  
Marat Yusupov
Keyword(s):  
Cell Growth ◽  
Small Molecules ◽  
Cancer Cells ◽  
Messenger Rna ◽  
Protein Biosynthesis ◽  
Structural Data ◽  
Anticancer Therapy ◽  
80S Ribosome ◽  
Molecular Bases ◽  
Major Target

Protein biosynthesis is a vital process for all kingdoms of life. The ribosome is the massive ribonucleoprotein machinery that reads the genetic code, in the form of messenger RNA (mRNA), to produce proteins. The mechanism of translation is tightly regulated to ensure that cell growth is well sustained. Because of the central role fulfilled by the ribosome, it is not surprising that halting its function can be detrimental and incompatible with life. In bacteria, the ribosome is a major target of inhibitors, as demonstrated by the high number of small molecules identified to bind to it. In eukaryotes, the design of ribosome inhibitors may be used as a therapy to treat cancer cells, which exhibit higher proliferation rates compared to healthy ones. Exciting experimental achievements gathered during the last few years confirmed that the ribosome indeed represents a relevant platform for the development of anticancer drugs. We provide herein an overview of the latest structural data that helped to unveil the molecular bases of inhibition of the eukaryotic ribosome triggered by small molecules.

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 Fawkner ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Small Molecules ◽  
Anticancer Therapy ◽  
Mechanisms Of Action ◽  
Allosteric Modulation ◽  
Structural Element ◽  
Allosteric Mechanism ◽  
Anti Cancer ◽  
P53 Activation ◽  
Pharmacological Potential

AbstractGiven the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

scholarly journals Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

ChemMedChem ◽  
2016 ◽  
Vol 11 (22) ◽  
pp. 2468-2473 ◽  
Author(s):  
Brian Budke ◽  
Wei Lv ◽  
Alan P. Kozikowski ◽  
Philip P. Connell
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Recent Developments

scholarly journals Evolving a Peptide: Library Platforms and Diversification Strategies

2019 ◽  
Vol 21 (1) ◽  
pp. 215 ◽  
Author(s):  
Krištof Bozovičar ◽  
Tomaž Bratkovič
Keyword(s):  
Small Molecules ◽  
Combinatorial Libraries ◽  
Library Design ◽  
Tissue Penetration ◽  
Biological Origin ◽  
Future Directions ◽  
Recombinant Peptide ◽  
New Developments ◽  
Pharmaceutical Ingredients ◽  
Diversification Strategies

Peptides are widely used in pharmaceutical industry as active pharmaceutical ingredients, versatile tools in drug discovery, and for drug delivery. They find themselves at the crossroads of small molecules and proteins, possessing favorable tissue penetration and the capability to engage into specific and high-affinity interactions with endogenous receptors. One of the commonly employed approaches in peptide discovery and design is to screen combinatorial libraries, comprising a myriad of peptide variants of either chemical or biological origin. In this review, we focus mainly on recombinant peptide libraries, discussing different platforms for their display or expression, and various diversification strategies for library design. We take a look at well-established technologies as well as new developments and future directions.

scholarly journals Nanoparticles for Ferroptosis Therapy in Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1785
Author(s):  
Nadia Zaffaroni ◽  
Giovanni Luca Beretta
Keyword(s):  
Drug Delivery ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Small Molecules ◽  
Tumor Targeting ◽  
Clinical Success ◽  
Anticancer Therapy ◽  
Regulated Cell Death ◽  
Targeting Ability ◽  
Available Information

Ferroptosis is a regulated cell death mechanism holding promise for anticancer therapy. Numerous small molecules inducing ferroptosis have been reported thus far. However, these compounds suffer from important drawbacks including poor solubility, systemic toxicity, and scarce tumor targeting ability that have limited their clinical success. The notion that nanoparticles inducing ferroptosis show better preclinical profiles compared to small molecules and overcome resistance to apoptosis has opened a new scenario for cancer treatment. Due to peculiar chemical-physical properties, nanoparticles can be loaded with anticancer drugs or decorated with tumor-selecting molecules. These features allow for drug combination treatment as well as tumor targeting. In the review, we summarize and discuss the available information concerning nanoparticles inducing ferroptosis endowed with different peculiarities and suitable for therapeutic purposes including nanoparticles for (i) antitumor drug delivery, (ii) tumor targeting, (iii) immunomodulation, and (iv) radiofrequency ablation, hyperthermia, and photodynamic therapy.

Discovery of small molecules targeting GRP78 for antiangiogenic and anticancer therapy

2020 ◽  
Vol 193 ◽  
pp. 112228 ◽  
Author(s):  
Yixue Qiao ◽  
Charlotte Dsouza ◽  
Abigail Ann Matthews ◽  
Yan Jin ◽  
Wan He ◽  
...  
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy
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