Drug discovery programs have traditionally focused on small molecules (molecular weight of <500 g/mol). However, for a significant number of drug targets, classical approaches are not feasible. For example, proteins without well-defined or with shallow binding pockets (e.g., those mediating protein–protein interactions) are difficult targets and, in many cases, even considered “undruggable.”1 In addition, the classical modulation of protein functions through small molecule agonists, antagonists, or inhibitors has inherent limitations due to its occupancy-based mode of action.2,3
Therefore, biologicals, mainly antibodies, have gained importance in recent years. They are well suited for modulating extracellular targets with high potency and selectivity; however, owing to their low membrane permeability, they usually cannot be employed to address intracellular targets and typically lack peroral and brain bioavailability.
With a dramatically growing knowledge in biology, and due to the limitations of classical approaches, novel strategies in medicinal chemistry and novel types of drugs/novel chemotypes (“new modalities”) have recently gained importance in drug research, discovery, and development.3−6
New therapeutic modalities include nonclassical representatives of (but are not limited to) the following chemotypes:
Nanobodies and (modified) antibodies
Oligo- and polypeptides (e.g., stapled and modified peptides)
Oligo- and polynucleotides (e.g., siRNAs, mRNAs, aptamers, gene therapeutics)
Polyglycosides
Macrocyclic molecules
Drug conjugates (e.g., antibody–drug conjugates, drug–drug conjugates, fluorescence-labeled drugs)
Targeted protein degraders (e.g., proteolysis-targeting chimeras (PROTACs) and molecular glues) that induce a chemical knockdown of proteins
Cellular therapies.
These new modalities possess properties beyond Lipinski’s rule of five for classical (peroral) drugs7 and allow extending the chemical space in drug discovery. Due to their particular physicochemical and pharmacokinetic properties, they come with specific challenges for medicinal chemists, (bio)analytical chemists, and pharmacologists.
The joint Virtual Special Issue on new drug modalities will collect the latest developments in this field related to medicinal chemistry, pharmacology, and translational science. Authors can choose one of the sister journals to submit their manuscript, depending on its main focus. The Editors may also offer transfer in case one or the other journal appears to be more appropriate.
The Virtual Special Issue format means that articles are placed into the next available regular journal issue shortly after acceptance, instead of being published in a dedicated issue. Once all articles for the collection have been accepted, they will be featured on a dedicated web page, giving additional exposure to each publication.
Please consider the relevant instructions to authors before submitting a manuscript. For ACS Pharmacology & Translational Science, different types of articles related to the topic are welcome, including Articles, Letters, Reviews and Mini-Reviews, Perspectives, Viewpoints, and Drug Discovery Stories. ACS Medicinal Chemistry Letters invites Letters, Innovations, Topical Innovations, Technology Notes, Notes, and Viewpoints. Journal of Medicinal Chemistry is interested in receiving original Research Articles, Perspectives, or Drug Annotations.
The submission deadline for all three journals is July 31, 2022. We are looking forward to your manuscripts. Please do not hesitate to send us a prepublication request in case you are not sure whether your manuscript would fit. The relevant journal offices can be reached via the following email addresses:
ACS Medicinal Chemistry Letters: eic@medchemlett.acs.org
ACS Pharmacology & Translational Science: eic@ptsci.acs.org
Journal of Medicinal Chemistry:jmc@jmedchem.acs.org
This Editorial is simultaneously published in ACS Pharmacology & Translational Science, ACS Medicinal Chemistry Letters, and Journal of Medicinal Chemistry. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
References
- Samarasinghe K. T. G.; Crews C. M. Targeted protein degradation: A promise for undruggable proteins. Cell. Chem. Biol. 2021, 28, 934–951. 10.1016/j.chembiol.2021.04.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schapira M.; Calabrese M. F.; Bullock A. N.; Crews C. M. Targeted Protein Degradation: Expanding the Toolbox. Nat. Rev. Drug Discovery 2019, 18, 949–963. 10.1038/s41573-019-0047-y. [DOI] [PubMed] [Google Scholar]
- Nalawansha D. A.; Crews C. M. PROTACs: An Emerging Therapeutic Modality in Precision Medicine. Cell Chem. Biol. 2020, 27, 998–1014. 10.1016/j.chembiol.2020.07.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valeur E.; Jimonet P. New Modalities, Technologies, and Partnerships in Probe and Lead Generation: Enabling a Mode-of-Action Centric Paradigm. J. Med. Chem. 2018, 61, 9004–9029. 10.1021/acs.jmedchem.8b00378. [DOI] [PubMed] [Google Scholar]
- Blanco M. J.; Gardinier K. M. New Chemical Modalities and Strategic Thinking in Early Drug Discovery. ACS Med. Chem. Lett. 2020, 11, 228–231. 10.1021/acsmedchemlett.9b00582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Borsari C.; Trader D. J.; Tait A.; Costi M. P. Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology. J. Med. Chem. 2020, 63, 1908–1928. 10.1021/acs.jmedchem.9b01456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lipinski C. A.; Lombardo F.; Dominy B. W.; Feeney P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Delivery Rev. 1997, 23, 3–25. 10.1016/S0169-409X(96)00423-1. [DOI] [PubMed] [Google Scholar]