How Protein - Small Molecule Interactions Could Reveal New Therapeutic Targets

Dr. Ivan Cornella-Taracido has spent the past 15 years working in the pharmaceutical industry, at the edges of chemistry and biology, investigating the interactions between proteins and small molecules for the development of novel therapies. Having recently joined Cedilla Therapeutics as VP of Chemical Biology and Proteomics, his current work is focused on understanding the inherent homeostasis of proteins through the application of chemical biology and proteomics methodologies, with the goal of target identification and drug discovery.

At SLAS Europe 2018, Cornella-Taracido chaired the event’s first “discovery track” session, which featured a number of presentations highlighting how evolving technologies influence early discovery efforts in biotech portfolios and academia, for the continued development of safe and effective drug targets. In this SelectScience^® interview, Cornella-Taracido talks about his new role, his experiences at SLAS Europe 2018, and his hopes for the future of drug discovery at Cedilla Therapeutics.

SS: Tell me about yourself and your new role at Cedilla Therapeutics

ICT: After completing my doctorate and postdoctoral studies in chemistry, I was introduced to the fascinating world of chemical biology, an interdisciplinary branch of science on the hinge between chemistry and biology. Chemical biologists working in biomedical research apply chemical tools and methodologies to interrogate how genes and proteins expressed in different cells work, and how they can be harnessed to identify novel therapeutic targets, biomarkers and drugs for treating disease. Over the past 15 years in pharma, I have really enjoyed teaming up with experts in other biomedical disciplines, across many disease areas, to study human genes, proteins and how all of them affect cellular phenotypes, as a proxy for understanding health and disease and, ultimately, to develop life-saving medicines.

Fast-forward to Cedilla. After working in the big pharma industry for a number of years I joined Cedilla Therapeutics, a three-month-old start-up backed by Third Rock Ventures (TRV). I'm a very new employee, having joined just a few weeks ago. TRV thrives on building new companies grounded in strong basic and translational science, with a bold strategic vision on the business and operational models. Cedilla was created with its own unique scientific spin: Harnessing protein homeostasis, that is the stability-instability equilibria of certain proteins in living cells, in order to identify novel points of intervention for therapeutic treatment. Our scientific strategy takes advantage of new developments in molecular and cell biology, biophysics and proteomics. Our initial therapeutic focus is oncology.

I joined Cedilla as the Vice President of Chemical Biology and Proteomics, to help create a product engine for interrogating both specific proteins and the totality of disease proteomes at omics scale and, in short, to try to understand the behaviors of proteins in different types of cells. I will be working very closely with the biology, biophysics and medicinal chemistry teams to identify targets that could lead us to new therapeutics. As part of the scientific management of the company, I will also contribute to the high-level strategy and other non-scientific responsibilities.

SS: Which new technologies will be key to your research?

ICT: That's a good question. From the standpoint of Cedilla, we are not basing our discovery engine on a single technology. It's more about bringing together experience in drug discovery, in oncology, in chemical biology, etc., that the team brings. There are a number of technologies, some new, some evolving and some well validated and tested, that we will deploy. Borrowing from the strong science that our five company founders bring to the table, we will leverage state-of-the-art precise genome editing, genomics, phenotypic screening, high-resolution quantitative mass spectrometry, biophysics and computational methodologies to interrogate cells, proteins and small molecule behaviors at the individual and systems levels.

As we have seen at SLAS, we will have to figure out what are the best systems and cell types to achieve our goals, in terms of throughput or translation ability — whether it's immortalized cancer cells or primary tumor-derived, grown into 2D or 3D. We will be adapting methods depending on the drug discovery stage and specific questions that need to be addressed. For certain targets, we will use thoroughly standardized methods that would allow us to screen as many compounds as possible, while for other applications we may go for lower throughput, using more translatable types of technologies. There will be no single technology to highlight as such, but a combination.

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SS: Tell us about the session that you chaired at SLAS Europe 2018

ICT: The session that I chaired was the first “discovery track” of SLAS Europe 2018. In discussing with the SLAS committee and conference chairs I decided to focus on technologies that help to advance the early discovery pipeline, both in academia and in industry. The selection of speakers reflected a variety of technologies, with the intention of giving the audience a little bit of a general overview of the cutting edge that is being applied at the early part of the pipeline in the first day of the conference.

To summarize the speakers, Alexey Rak, from Sanofi, presented a great overview of state-of-the-art biophysical methods and their applications to lead optimization and drug discovery. Hinrich Goehlmann, from Janssen Research, presented a beautiful case of the use of high-throughput transcriptomics to annotate screening collections. Alleyn Plowright presented a number of examples around the use of stem cells as disease models, with considerations for their use in screening campaigns, and also techniques and approaches to mechanism of action, deconvolution and target identification. Jarrod Walsh, from AstraZeneca, presented on a particular case of oligonucleotides and how to advance screening with challenging assay optimization parameters. Finally, we had a student, Patrick Gentry, from the University of Copenhagen, who was granted a studentship to attend SLAS. His academic group in the University of Copenhagen is doing some terrific work and he presented a very nice case of “deorphaning” G-protein-coupled receptors (GPCRs). These are the largest and most diverse group of membrane-embedded proteins. These receptors are present at the surface of cells and act like an inbox and courier for messages to the cell, in the form of different types of physicochemical stimuli, such as peptides, lipids, sugars, small molecules, etc. They are very interesting proteins because of their very well-established use for therapeutics, but also because many of them are still “orphan”, meaning that we don’t know yet which stimuli turn them on and off, and how they signal. This fact makes it very difficult to develop structural and pharmacological approaches to study them, but it also provides exciting opportunities for breakthroughs.

SS: What do you see for the future of drug discovery?

ICT: I know that it sounds cliché, but having been in big pharma for most of my career and now having moved to a small start-up setting, I can see that the future of drug discovery depends more than ever on effective collaboration among different types of organizations. Large organizations historically tended to look inwards, to think about what can be advanced on your own, mainly because of intellectual property reasons, but it's demonstrated, again and again, that the only way to tackle the biggest challenges that lie ahead, to make a difference for patients, is through continuous collaboration. We are moving into a more heterogeneous landscape where academia is embarking on hit identification and the early steps of drug discovery. Industry is tending more to academia, not only for talent and basic science ideas, but also for access to more sophisticated disease models. And then there are the “world of data giants” dipping into this pool.

Successful, continuous reverse translational medicine, bringing findings from the doctor at the bedside back to the scientist bench, is the last frontier. We don't fully understand human biology, so the biggest challenge will continue to be to really understand how we are made and the how and why of when things go wrong with our bodies. As we add granularity, we are also adding challenges. Not so long ago, we used to treat cancer only with radiation and cytotoxics. As you move to personalized medicine, you have to expect that you are going to start to get patient populations in smaller cohorts to make them more targetable by certain types of therapies based on the genetic make-up of the population. This is true across the disease board, not only for oncology but also for neurodegeneration, autoimmune diseases, cardiomyopathies, etc. The treatment that works for you may do more harm to my daughter, with the same condition. We will continue to face unforeseen effects of drugs while we do not understand the biology at that basic level of genes, proteins and cells.

So, what else the future brings? The closing speaker at SLAS, Peter Hinssen, from Nexxworks, summarized it very eloquently. He gave a terrific overview of “The Day After Tomorrow” and urged all of us to pay special attention to the impact and promise of all things digital on society in general, and healthcare and drug discovery in particular. That future is now, and the organization that doesn’t embrace it will fall behind. It was the perfect closing for a great conference. I walked away uplifted and excited to help to shape that future!