Drug Design, Development and Therapy

Advances in p53 Drug Discovery

Often referred to as the "guardian of the genome", p53 plays an important role in maintaining cellular homeostasis by regulating and orchestrating cell cycle arrest, DNA repair, apoptosis, and senescence. Mutations in the TP53 gene which encodes p53, are found in a broad range of human cancers, leading to loss of its tumor-suppressive functions and contributing to cancer progression and metastasis. In addition, some gain-of-function (GOF) p53 mutants can acquire new oncogenic activities affecting genomic instability, metabolic reprogramming, and the tumor microenvironment, while promoting invasion, metastasis, and cancer cell proliferation. The complexity of p53's structure and function, particularly its role as a transcription factor and its interactions with a large number of cellular signalling pathways, has made it a challenging target for drug discovery. However, recent advances in structural biology, computational methods, and medicinal chemistry have opened new avenues for the development of drugs that can restore or enhance p53 function, offering hope for more effective cancer therapies. Furthermore, additional targets, such as MDM2/X, HAUSP, Cop-1, Pirh-2, Wip-1, PTEN, AKT, and Siah-1, could become points of therapeutic intervention, influencing p53 and its signalling and regulation network.

Playing a core role in tumor suppression, the ability to modulate p53 activity holds the potential to transform cancer treatment. The development of drugs that can restore the function of mutant p53 or enhance the activity of wild-type p53 is a critical area of research with significant implications for improving patient outcomes and survival rates in cancer.

To help raise the profile of this important area of research, Drug Design, Development and Therapy is publishing a timely Article Collection on p53 drug discovery. The Collection is led by Dr. Andreas Joerger, Prof. Dr. Alexander Dömling, and the Editor in Chief, Prof. Dr. Frank Boeckler.

Potential topics include, but are not limited to, the following:

• Structural and Molecular Biology of p53 Elucidating its Therapeutic Value
• Small Molecule Modulators of Targets Involved in p53 Signalling and Regulation
• Rescue of Loss-of-function Mutant p53 or Restraint of Gain-of-function Mutant p53
• p53-targeted Gene / Immune Therapies
• Clinical Translation of p53-based Therapies
• Challenges and Future Directions

Please submit your manuscript on our website, using the promo code XITLT for 20% off the advertised article processing charge and to indicate that your manuscript will be considered for the “Advances in p53 Drug Discovery” Collection. Please review the journal’s aims and scope and author submission instructions prior to submitting a manuscript.

Please contact Haoyang Yi (Commissioning Editor) at [email protected] with any queries regarding this Article Collection.

Guest Advisors

Dr. Andreas Joerger, Goethe University

[email protected]

Andreas C. Joerger obtained his doctoral degree from the University of Freiburg, Germany in 2000. He then assumed a postdoc position in the group of Prof. Sir Alan Fersht at the Medical Research Council (MRC) Centre for Protein Engineering in Cambridge, United Kingdom, initially working on protein design. He stayed on as a senior scientist in structural biology until 2010, before moving to the MRC Laboratory of Molecular Biology in Cambridge (2010-2015). During his long spell at the MRC, he made key contributions towards unraveling the complex structural biology of the tumor suppressor p53 and related proteins. He determined the first crystal structures of p53 cancer mutants, which led to the Y220C mutant being used as a paradigm for the development of mutant p53 rescue drugs based on protein stabilization. In 2016, Dr. Joerger joined the group of Prof. Stefan Knapp at the Institute of Pharmaceutical Chemistry at Goethe University, Frankfurt am Main. Since 2018, he is Principal Investigator on p53 drug discovery and transcriptional regulation at the Structural Genomics Consortium (SGC) Frankfurt. His other research interests include the evolutionary history of the p53 pathway, protein design, epigenetic targets and E3 ubiquitin ligases.

Dr. Alexander Dömling, Palacky University in Olomouc

[email protected]

Alex Dömling studied Chemistry & Biology at the Technische Universitat Munchen (TUM). He performed his Ph.D. with Ivar Ugi and his postdoc – funded by a Feodor Lynen stipend from the Alexander von Humboldt Foundation – with double Nobel Laureate Barry Sharpless. After his habilitation at TUM, he became a professor at the University of Pittsburgh, then chair of the Department of Drug Design at the University of Groningen, and most recently ERA Chair at Palacky University. He also started several biotech companies. He is the author of over 300 publications and over 70 patent applications. His current lab works according to the mantra ‘Automation + Miniaturization = Acceleration’ on the ERC-funded project of engineering an autonomous drug discovery platform called AMADEUS.

Alexander Dömling is a world-renowned researcher in the area of miniaturization, automation of synthetic chemistry, and multicomponent reaction chemistry. Professor Dömling applies multicomponent reaction chemistry to solve problems in drug discovery and related areas. Notably, he introduced the Acoustic Droplet Ejection technology platform to perform precise high throughput synthetic chemistry and demonstrated its applicability to multiple different chemistries and chemical biology projects.

Dr. Frank M. Böckler, Eberhard Karls University Tübingen

[email protected]

At the Institute of Pharmaceutical Sciences, Frank Böckler heads the laboratory of Molecular Design & Pharmaceutical Biophysics, which combines Chemical Biology, Molecular and Structural Biology and Biophysics, as well as Computational Chemistry, Machine Learning and Molecular Design. In addition, he is a member of the Institute for Bioinformatics and Medical Informatics (IBMI). In 2004, he received his Ph.D. in Medicinal Chemistry with summa cum laude at Friedrich-Alexander University in Erlangen (Germany). Joining Prof. Sir Alan R. Fersht as a postdoc at the MRC Center for Protein Engineering in Cambridge/UK, he discovered p53 mutant stabilizers as potential new cancer therapeutics. In 2008, he was appointed Professor (W2tt) for Bioanalytics at Ludwig-Maximilians University (LMU) Munich, before moving to Tübingen in 2010 as a full professor. His work is dedicated to understanding molecular interactions, such as halogen and chalcogen bonds, as the foundation for chemical biology and drug discovery and to apply theoretical, fragment-based, biophysical, and structural methods to cancer research, particularly involving the human kinome and the network of the tumor suppressor p53.