ABSTRACT
For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.
Subject(s)
Antineoplastic Agents , Chalcones , Cyclooxygenase 2 Inhibitors , Neoplasm Proteins , Neoplasms , Protein Kinase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/chemistry , Chalcones/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , Humans , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacologyABSTRACT
Targeted protein degradation (TPD), discovered twenty years ago through the PROTAC technology, is rapidly developing thanks to the implication of many scientists from industry and academia. PROTAC chimeras are heterobifunctional molecules able to link simultaneously a protein to be degraded and an E3 ubiquitin ligase. This allows the protein ubiquitination and its degradation by 26S proteasome. PROTACs have evolved from small peptide molecules to small non-peptide and orally available molecules. It was shown that PROTACs are capable to degrade proteins considered as "undruggable" i.e. devoid of well-defined pockets and deep grooves possibly occupied by small molecules. Among these "hard to drug" proteins, several can be degraded by PROTACs: scaffold proteins, BAF complex, transcription factors, Ras family proteins. Two PROTACs are clinically tested for breast (ARV471) and prostate (ARV110) cancers. The protein degradation by proteasome is also induced by other types of molecules: molecular glues, hydrophobic tagging (HyT), HaloPROTACs and homo-PROTACs. Other cellular constituents are eligible to induced degradation: RNA-PROTACs for RNA binding proteins and RIBOTACs for degradation of RNA itself (SARS-CoV-2 RNA). TPD has recently moved beyond the proteasome with LYTACs (lysosome targeting chimeras) and MADTACs (macroautophagy degradation targeting chimeras). Several techniques such as screening platforms together with mathematical modeling and computational design are now used to improve the discovery of new efficient PROTACs.
TITLE: Dégradation induite des protéines par des molécules PROTAC et stratégies apparentées : développements à visée thérapeutique. ABSTRACT: Alors que, pour la plupart, les médicaments actuels sont de petites molécules inhibant l'action d'une protéine en bloquant un site d'interaction, la dégradation ciblée des protéines, découverte il y a une vingtaine d'années via les petites molécules PROTAC, connaît aujourd'hui un très grand développement, aussi bien au niveau universitaire qu'industriel. Cette dégradation ciblée permet de contrôler la concentration intracellulaire d'une protéine spécifique comme peuvent le faire les techniques basées sur les acides nucléiques (oligonucléotides antisens, ARNsi, CRISPR-Cas9). Les molécules PROTAC sont des chimères hétéro-bifonctionnelles capables de lier simultanément une protéine spécifique devant être dégradée et une E3 ubiquitine ligase. Les PROTAC sont donc capables de provoquer l'ubiquitinylation de la protéine ciblée et sa dégradation par le protéasome 26S. De nature peptidique, puis non peptidique, les PROTAC sont maintenant administrables par voie orale. Ce détournement du système ubiquitine protéasome permet aux molécules PROTAC d'élargir considérablement le champ des applications thérapeutiques puisque l'élimination de protéines dépourvues de poches ou de crevasses bien définies, dites difficiles à cibler, devient possible. Cette technologie versatile a conduit à la dégradation d'une grande variété de protéines comme des facteurs de transcription, des sérine/thréonine/tyrosine kinases, des protéines de structure, des protéines cytosoliques, des lecteurs épigénétiques. Certaines ligases telles que VHL, MDM2, cereblon et IAP sont couramment utilisées pour être recrutées par les PROTAC. Actuellement, le nombre de ligases pouvant être utilisées ainsi que la nature des protéines dégradées sont en constante augmentation. Deux PROTAC sont en étude clinique pour les cancers du sein (ARV471) et de la prostate (ARV110). La dégradation spécifique d'une protéine par le protéasome peut aussi être induite par d'autres types de molécules synthétiques : colles moléculaires, marqueurs hydrophobes, HaloPROTAC, homo-PROTAC. D'autres constituants cellulaires sont aussi éligibles à une dégradation induite : ARN-PROTAC pour les protéines se liant à l'ARN et RIBOTAC pour la dégradation de l'ARN lui-même comme celui du SARS-CoV-2. Des dégradations induites en dehors du protéasome sont aussi connues : LYTAC, pour des chimères détournant la dégradation de protéines extracellulaires vers les lysosomes, et MADTAC, pour des chimères détournant la dégradation par macroautophagie. Plusieurs techniques, en particulier des plates-formes de criblage, la modélisation mathématique et la conception computationnelle sont utilisées pour le développement de nouveaux PROTAC efficaces.
Subject(s)
COVID-19 Drug Treatment , Drug Design , Molecular Targeted Therapy/methods , Proteolysis , Recombinant Fusion Proteins/pharmacology , SARS-CoV-2/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Autophagy , Catalysis , Humans , Lysosomes/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Proteasome Endopeptidase Complex/metabolism , Protein Conformation , Protein Processing, Post-Translational/drug effects , Protein Stability , Proteolysis/drug effects , RNA/drug effects , RNA-Binding Proteins/antagonists & inhibitors , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/pharmacokinetics , Structure-Activity Relationship , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.
Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Prostatic Neoplasms/epidemiology , Sex Distribution , Angiotensin-Converting Enzyme 2 , Antineoplastic Agents, Hormonal/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Disease Susceptibility , Drug Repositioning , Female , Forecasting , Gonadal Steroid Hormones/physiology , Humans , Male , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/physiology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Protease Inhibitors/therapeutic use , Receptors, Virus/drug effects , Receptors, Virus/physiology , Risk Factors , SARS-CoV-2 , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/physiology , United States/epidemiology , Virus InternalizationABSTRACT
The mapping of SARS-CoV-2 human protein-protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host-virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.