Identification and characterization of cancer vulnerabilities via targeted protein degradation
Publication date: Available online 2 January 2019Source: Drug Discovery Today: TechnologiesAuthor(s): Cristina Mayor-Ruiz, Georg E. WinterTarget(ed) protein degradation (TPD) is a novel paradigm in drug discovery and a promising therapeutic strategy. TPD is based on small-molecules that catalyze the degradation of proteins by re-directing the ubiquitination activity of ubiquitin E3 ligases. Its unique molecular pharmacology enables robust, selective and fast elimination of proteins in cellular assays and in vivo. In addition to possible clinical applications, TPD is also emerging as an attractive alternative to traditional...
Source: Drug Discovery Today: Technologies - January 3, 2019 Category: Drugs & Pharmacology Source Type: research
Monitoring and deciphering protein degradation pathways inside cells
Publication date: Available online 19 December 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Danette L. Daniels, Kristin M. Riching, Marjeta UrhA new series of therapeutic modalities resulting in degradation of target proteins, termed proteolysis targeting chimeras (PROTACs), hold significant therapeutic potential with possible prolonged pharmacodynamics, improved potency, and ability to target proteins previously thought of as “undruggable”. PROTACs are heterobifunctional small molecules consisting of a target binding handle bridged via a chemical linker to an E3 ligase handle which recruit the E3 ligase an...
Source: Drug Discovery Today: Technologies - December 19, 2018 Category: Drugs & Pharmacology Source Type: research
Antibody – Drug conjugates (ADC) – Drug discovery today: Technologies
Publication date: December 2018Source: Drug Discovery Today: Technologies, Volume 30Author(s): Vijay Chudasama (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - December 13, 2018 Category: Drugs & Pharmacology Source Type: research
Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: Is mechanism related to systemic toxicity?
This article discusses the observed toxicities in relation to the structures and mechanisms of action of payload type. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - December 6, 2018 Category: Drugs & Pharmacology Source Type: research
Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy
Publication date: Available online 30 November 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Michael C. Johnston, Christopher J. ScottAntibody conjugated nanoparticles (ACNPs) represent a novel strategy for the development of therapies exploiting antibodies to augment the delivery of chemotherapy payloads. Following in the footsteps of the success of antibody drug conjugates (ADCs), ACNPs are only now reaching clinical evaluation. In this review we discuss the success of ADCs and explore the opportunities ACNPs offer, such as broad chemotherapy payload selection, high drug to antibody ratios and the ability to f...
Source: Drug Discovery Today: Technologies - December 1, 2018 Category: Drugs & Pharmacology Source Type: research
Ligand-induced genetic degradation as a tool for target validation
Publication date: Available online 24 November 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Aisha Yesbolatova, Yusuke Tominari, Masato T. KanemakiTargeted protein degraders, known as proteolysis targeting chimeras (PROTACs), are drawing more attention as next-generation drugs to target currently undruggable proteins. As drug discovery of functional degraders involves time- and cost-consuming laborious processes, we propose employing a ligand-induced genetic degradation system to validate candidate proteins before degrader development. Genetic degradation mimics degrader treatment by depleting a degron-fused pro...
Source: Drug Discovery Today: Technologies - November 25, 2018 Category: Drugs & Pharmacology Source Type: research
Multicomponent reactions in drug discovery and medicinal chemistry
Publication date: November 2018Source: Drug Discovery Today: Technologies, Volume 29Author(s): Eelco Ruijter, Romano Orru, Synthetic and BioOrganic Chemistry Group (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - November 22, 2018 Category: Drugs & Pharmacology Source Type: research
Exploring alternative antibody scaffolds: Antibody fragments and antibody mimics for targeted drug delivery
Publication date: Available online 8 November 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Daniel A. RichardsThe field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. in antibody–drug conjugates (ADCs). The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community; many major companies have dedicated ADC research programmes. However, despite the advantages, the field of ADCs has failed to...
Source: Drug Discovery Today: Technologies - November 9, 2018 Category: Drugs & Pharmacology Source Type: research
Drawing lessons from the clinical development of antibody-drug conjugates
Publication date: Available online 24 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Robert LyonThe antibody-drug conjugate (ADC) field has seen a remarkable expansion in the number of entrants in clinical studies. Many of these agents employ newer conjugation technologies that have been developed over the last decade that confer various attributes to the ADCs prepared with them, including stability, potency, and homogeneity. In many cases, these new ADCs appear demonstrably superior to earlier technologies in preclinical models of activity and toxicology, but the degree to which these improvements will t...
Source: Drug Discovery Today: Technologies - October 25, 2018 Category: Drugs & Pharmacology Source Type: research
Site-specific chelator-antibody conjugation for PET and SPECT imaging with radiometals
Publication date: Available online 24 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Mauricio Morais, Michelle T. MaAntibodies and their derivatives radiolabelled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo. Chelators that are covalently attached to antibodies allow radiolabelling with metallic PET and SPECT radioisotopes. Conventional strategies for chelator-protein conjugation generate heterogeneous mixtures of bioconjugates that...
Source: Drug Discovery Today: Technologies - October 25, 2018 Category: Drugs & Pharmacology Source Type: research
Miniaturised ‘antibody’-drug conjugates for solid tumours?
Publication date: Available online 17 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Mahendra P. DeonarainWith Antibody-Drug Conjugate strategies firmly focussed on the precise conjugation to the large protein Immunoglobulin-G format, it is easy to miss the more recent technological innovations in small-format drug conjugates. Here, the targeting ligand can be at 50–95% reduced in size, or even smaller if peptidic in nature. Antibody domains or alternative binding scaffolds, chemically-modified with ultra-potent cytotoxic payloads offer an alternative approach for oncology therapeutics, promising a wide...
Source: Drug Discovery Today: Technologies - October 18, 2018 Category: Drugs & Pharmacology Source Type: research
Homogeneous antibody-drug conjugates via site-selective disulfide bridging
Publication date: Available online 12 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Nafsika Forte, Vijay Chudasama, James R. BakerAntibody-drug conjugates (ADCs) constructed using site-selective labelling methodologies are likely to dominate the next generation of these targeted therapeutics. To this end, disulfide bridging has emerged as a leading strategy as it allows the production of highly homogeneous ADCs without the need for antibody engineering. It consists of targeting reduced interchain disulfide bonds with reagents which reconnect the resultant pairs of cysteine residues, whilst simultaneously...
Source: Drug Discovery Today: Technologies - October 13, 2018 Category: Drugs & Pharmacology Source Type: research
Enzymatic strategies for (near) clinical development of antibody-drug conjugates
Publication date: Available online 11 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Sander S. van Berkel, Floris L. van DelftAbstractTarget-specific killing of tumor cells with antibody-drug conjugates (ADCs) is an elegant concept in the continued fight against cancer. However, despite more than 20 years of clinical development, only four ADC have reached market approval, while at least 50 clinical programs were terminated early. The high attrition rate of ADCs may, at least in part, be attributed to heterogeneity and instability of conventional technologies. At present, various (chemo)enzymatic approach...
Source: Drug Discovery Today: Technologies - October 12, 2018 Category: Drugs & Pharmacology Source Type: research
Bispecifics and antibody–drug conjugates: A positive synergy
Publication date: Available online 11 October 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Antoine MaruaniBispecific antibodies (BsAbs) are antibodies with two different paratopes. In the past decade, advances in protein engineering have enabled the development of more than 100 formats of BsAbs. With two BsAbs approved for therapeutic use and more than 60 in clinical trials, this research area has shifted from being effervescent to being a mainstream therapeutic development topic. In parallel, recent progress in protein conjugation and cytotoxicity of small molecule drugs has resulted in a boom in monospecific ...
Source: Drug Discovery Today: Technologies - October 11, 2018 Category: Drugs & Pharmacology Source Type: research
Amanitins and their development as a payload for antibody-drug conjugates
Publication date: Available online 24 September 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Andreas Pahl, Christian Lutz, Torsten HechlerAmanitin-based ADCs represent a new class of ADCs using a novel mode of action. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA Polymerase II. The high potency of the toxin leads to highly efficacious ADCs. The development of the technology around this toxin will be described. These developments support the clinical development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index. ...
Source: Drug Discovery Today: Technologies - October 5, 2018 Category: Drugs & Pharmacology Source Type: research
