2021 PROTACs Workshop Summary

A consistent theme has dominated the discussions that take place during our yearly workshops: discovery programs are investigating compounds that lie in the Bro5 chemical space. These molecules can be peptides, macrocycles, or proteolysis targeting chimeras (PROTACs). This year, we chose to highlight physicochemical properties as they relate to PROTACs. Registration this year was at an all-time high, with a final count of 210 registrants. Most registrants came from the pharmaceutical industry (62%) followed by academia (28%).

PROTACs consist of three components: a ligand that binds to a target protein, a ligand that binds to a an E3 ubiquitin ligase, and a linker chain connecting the two. While small molecules are designed to inhibit protein activity by binding to a specific site on a target protein, PROTACs are designed to bring the protein of interest and an E3 ubiquitin ligase close enough together to form a ternary complex. This formation causes the ubiquitination of the target protein, resulting in the degradation of the target protein via the proteosome. Their mechanism of action allows them to be active within the cell for longer durations and at significantly lower concentrations than the traditional small molecule, but designing a PROTAC that can successfully enter a cell is a top challenge.

PROTACs are large compounds (MW > 1000 Da), and can fold and contort their structures based on the environment they’re in. A poll conducted at the beginning of the workshop showed a unanimous consensus that while permeability is the most important property to consider in PROTAC design, it is also the most challenging to measure experimentally due their large size, poor solubility, and tendency to stick to labware.

The presentations this year offered insight on how to measure PROTAC permeability as well as optimize it. PAMPA, MDCK, and Caco-2 were universally cited as a starting point to assess permeability in-vitro, however none of them consistently correlate with cell permeability. Lipophilicity and solubility measurements should also be considered given their impact on permeability. Stability in plasma was also mentioned, as optimizing PROTACs for permeability can negatively affect the stability of the ternary complex and reduce PROTAC function.

After 2 days of presentations from PROTAC experts and roundtable dialogue among the participants, one thing is certainly clear: research about the discovery and design of PROTACs has only just begun, and breakthroughs are made when industry and academia work together to solve common problems. Due to the lack of experimental data available for PROTACs, we are far from being able to predict their physicochemical properties, however we hope to continue to drive the discussion around the importance of considering physicochemical properties when designing them.

References

Pike, et al., 2020. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discovery Today. 25, 1793-1800.

F. Begnini, et al. 2021. Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies. ACS Med. Chem. Lett. 12, 6, 983-990.

G. Ermondi et al., 2021. Rational Control of Molecular Properties Is Mandatory to Exploit the Potential of PROTACs as Oral Drugs. ACS Med. Chem. Lett. 12, 1056-1060.

V.G. Klein, et al., 2020. Understanding and Improving the Membrane Permeability of VH032-Based PROTACs. ACS Med. Chem. Lett. 11, 1732-1738.

V. Poongavanam and J. Kihlberg, 2021. PROTAC cell permeability and oral bioavailability: a journey into uncharted territory. Future Medicinal Chemistry. Epub ahead of print.

Workshop Speakers

Jan Kihlberg

Uppsala University

Alessio Cuilli

University of Dundee

Brian Cook

Vividion Therapeutics

Giulia Caron

University of Torino

Scott Lokey

University of California Santa Cruz

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3615 Superior Ave. E #4407B

Cleveland, OH 44114 

© All Rights Reserved 2022

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3615 Superior Ave. E #4407B
Cleveland, OH 44114
(216)432-9050
info@analiza.com

Professor

Uppsala University

Jan Kihlberg holds a chair in Organic Chemistry at Uppsala University, Sweden since 2013. Before moving to Uppsala he spent ten years at AstraZeneca R&D in Gothenburg, first as Director of Medicinal Chemistry and then as Director of Competitive Intelligence and Business Foresight Analysis. Prior to that he was Professor in Organic Chemistry at Umeå University during 1996-2003, after leaving Lund University where he established his independent research group in 1991. Professor Kihlberg’s main research interests is to understand what properties convey cell permeability, aqueous solubility and target binding to drugs and PROTACs in the beyond rule of 5 chemical space and to translate this knowledge into guidelines for design. He is also involved in synthesis of macrocycles as ligands for difficult-to-drug targets, and of glycopeptides and peptides for use in diagnostics and treatments for rheumatoid arthritis. He has published 168 peer reviewed articles, 17 research reviews and four book chapters.

Professor

University of Dundee

Alessio Ciulli holds the Personal Chair of Chemical Structural Biology at the School of Life Sciences, University of Dundee. He is also the Director of the newly announced Dundee’s Centre for Targeted Protein Degradation (CeTPD). Dr Ciulli’s laboratory has made important contributions to selective chemical intervention on protein-protein interactions targets and to the development of proteolysis-targeting chimeric molecules (PROTACs) as a viable strategy for targeted protein degradation. Amongst his most significant discoveries are the fragment-based design of ligands for the E3 ligase von Hippel-Lindau (VHL), and their use to design one of the first VHL-based PROTACs: the BET degrader MZ1. Dr Ciulli’s Lab later illuminated fundamental insights into PROTACs’ mechanism of action, solving the first crystal structure of a PROTAC ternary complex. Dr. Ciulli is the scientific founder of Amphista therapeutics, a company that develops new protein degradation platforms. Before joining Dundee, Dr Ciulli was a group leader at the University of Cambridge, where he previously earned his PhD degree and carried out postdoctoral research. Amongst his honours are the EFMC Prize for Young Medicinal Chemist in Academia, the ICBS young chemical biologist award, the RSC Capps Green Zomaya Award in medicinal computational chemistry, and election as Fellow of the Royal Society of Chemistry.

Senior Director

Vividion Therapeutics

Brian Cook completed his Ph. D. with Carolyn Bertozzi at the University of California at Berkeley, working on carbohydrate sulfotransferases involved in the immune response. He started his industrial career at Boehringer Ingelheim in Ridgefield, CT. Over the next 15 years, he worked on a number of projects in the immunology and cardiometabolic disease areas. He also worked in the early lead discovery group, looking at novel lead finding modalities to enable new projects. After Boehringer-Ingelheim, he worked at the Yale Center for Molecular Discovery before moving on to Vividion Therapeutics in San Diego where he is currently a Senior Director in the chemistry department.

Professor

University of Torino

Giulia studied at the University of Torino (Italy) where she received a B.Sc. in Pharmaceutical Chemistry and Technology in 1992, and a B.Sc. in Pharmacy in 1994. Then she moved to the University of Lausanne (Switzerland) where in 1997 she obtained her PhD in Pharmaceutical Sciences under the supervision of prof. B. Testa. From 1999 to 2014 Giulia was Assistant Professor at the University of Torino where now she holds the position of Associate Professor at the Molecular Biotechnology and Health Sciences Department.
Her primary scientific activity was lipophilicity, then she moved to the design, experimental determination and computational prediction of physicochemical descriptors related to solubility, permeability and ADME properties. The integration of Intramolecular Hydrogen Bonding (IMHB) considerations in drug design and lead optimization is one of her main field of interest. Recently, Giulia is deeply focusing on the beyond rule of 5 (bRo5) chemical space since efficient property‑based drug design and optimization are essential to discover bRo5 candidates with the right solubility and permeability profiles. A major challenge in this scenario is represented by the chameleonic properties exhibited by some bRo5 compounds which can adapt their conformation to the environment and prefer the closed form in apolar environments and the open form in aqueous media. A rational control of the chameleonic properties of bRo5 compounds is therefore Giulia’s major interest in these days.

Professor

University of California Santa Cruz

Scott Lokey received his Ph.D. at the University of Texas, Austin in organic chemistry, where his research centered on the synthesis of molecules that fold into protein-like shapes in water and bind to specific DNA sequences. He did post-doctoral research at Genentech, where he worked on the synthesis of bioactive cyclic peptides, and then at Harvard Medical School on the synthesis of molecules designed to disrupt cellular processes related to motility. He joined the faculty at UCSC in 2002 in the Department of Chemistry and Biochemistry, where his research group focuses on the relationship between molecular structure and drug-like properties, especially cell permeability. Professor Lokey is also the director of the UCSC Chemical Screening Center, a high-throughput screening facility dedicated to early stage lead discovery, and is co-founder of Circle Pharma, a biotech startup focusing on the discovery of cyclic peptide inhibitors against intracellular targets.