"As a company we all have to have a phenotypic drug discovery mindset, which means that we have to be prepared for any target (or working on an unknown target) that acts through any compartment (liver, CNS, etc) that modulates physiological endpoints for any disease. I’m no longer a target-based medicinal chemist working on metabolic diseases, I’m a phenotypic drug discovery scientist working on circadian modulators that are disease agnostic. It’s an exciting, challenging and hugely rewarding part of my career and I am relishing working with the Reset team to create a new path for drug discovery in this novel scientific area."
Paul Humphries, Ph.D.
Dr. Humphries is the Vice President, Chemical Sciences at Reset Therapeutics. Previously, he was a Senior Principal Scientist at Pfizer working in the area of Metabolic Diseases. While at Pfizer, Dr. Humphries worked on programs resulting in seven Investigational New Drug (IND) submissions to the U.S. Food and Drug Administration across four late stage projects. He was also responsible for numerous go/no go decisions on early stage projects. Dr. Humphries has authored more than 25 scientific articles and patents on a wide range of topics/drug targets and received the Pfizer Global Rand Achievement Award in 2005.
Over the course of his Pfizer career, Dr. Humphries led or was a member of many successful project teams. These teams were instrumental in the discovery and development of investigational molecules with potential utility in the treatment of cancer, diabetes, metabolic syndrome, and osteoporosis. He received his Ph.D. from the University of Sheffield in the UK and performed postdoctoral research at Florida State University.
Interviewed by Collaborative Drug Discovery, Inc.
Tell me about the specific challenges to working with circadian rhythm altering therapies. I’m sure the endpoints and biomarkers must be quite unique.
There are definitely more difficult challenges associated with working on circadian rhythm modulators compared to target-based projects where your target is perceived to be constantly expressed over 24hrs. I also think that there is a lot of circadian science that is ignored in big pharma even for target-based projects. For example numerous detoxifying pathways are circadian so drugs are metabolized at different rates depending on when they are dosed, physiological pathways are circadian and there are numerous papers on time of day dosing affecting efficacy and safety of oncology drugs in particular (chronopharmacology), etc.
Our primary assays (which are performed by Tod Steinfeld and Eric Mabery) are phenotypic, which obviously carries their own challenges, where we utilize cell lines carrying core clock proteins attached to a luciferase reporter. The first challenge is that the assay needs to be run for 4-5 days in order to monitor the circadian rhythm changes that occur over a longer time-frame. We initially run a high content assay with a smaller diverse set of compounds, though a HTS utilizing a very large number of compounds is not out of the question. The assays allow us to monitor the period, phase, and amplitude, of the circadian rhythms, and so we need to utilize some proprietary software in order to capture and process all the data prior to uploading into the CDD Vault. Once there, we can then analyze the phenotypes of small molecule modulators and look for trends.
Once we identify compounds with a phenotype that we predict will be useful for disease therapies, (e.g. amplitude enhancers for diseases of aging – circadian rhythms dampen as people get older), then we can utilize the phenotypic assay for doing medicinal chemistry and following SAR. This is not always straightforward but our Cryptochrome modulator project – in which we have taken novel circadian-modifying compounds from hits to animal POC in metabolic diseases – demonstrates how Reset has reduced this to practice. In parallel, the in-vitro biology group performs target deconvolution, which is another challenge associated with performing med chem via phenotype.
Once we know our target, we obviously have to perform studies linking the target to the disease. The target is circadian, so we know that its expression varies over 24hrs, and thus we need to perform studies (which are performed by Kerryn McCluskie, Travis Renner and Erik Willis) looking at time-of-day dependence of efficacy (chronopharmacology). We also look at time-of-day dependence of our compound metabolism and also the time-of-day dependence of the endpoints that we are measuring (e.g. OGTT for type 2 diabetes). The hard part is putting these three pieces of information together, during the period of intersect for the three parts of the Venn diagram.
All of the above is performed in cells, tissues, or rodents, so we then need to map this onto what we know about circadian rhythms in humans (our ultimate patient) and adjust the scientific theory accordingly.
Reset Therapeutics has utilized the last two years to build a scientific foundation that allows us to overcome all of the above challenges, and boil it down into a manageable, industrialized, and reproducible critical path. This platform is the engine that produces all of our projects that can address multiple diseases of circadian desynchrony (e.g. cardiovascular, metabolic, cancer and CNS diseases).
You have some brilliant minds on your SAB. How does Reset effectively get the most out them?
Everybody that is on the Reset SAB was on the original Think Tank that occurred back in 2008. Reset has utilized technologies and science from all of their labs, and so we have been in constant contact with them since the beginning, in order to set up the science in our own labs, and industrialize them. We have sent multiple Reset employees to their labs for scientific discussions and exposure to the leading edge of exploring the links between molecular clocks and various disease pathologies. We have two SAB meetings per year, which is another opportunity to take in their communal expertise, and we also have constant email contact in order to provide updates. This team is not just names on a paper, but part of the fabric of Reset and definitely part of our scientific advantages, compared to anybody else that would like to enter the circadian drug discovery space.
Your metabolic programs are targeted to the cryptochromes in the liver and your narcolepsy orexin receptors in the hypothalamus. These are both related to circadian rhythms, but are very different therapeutically. How do you manage two very different, yet similar therapeutic areas?
Coming from Pfizer with many years of metabolic disease expertise, the Cry project aimed at peripheral modulation of circadian rhythms comes very natural to me. The Orexin project for narcolepsy is the one that is out of my comfort zone and so I spent a lot of time immersing myself into the CNS drug discovery space when I first joined Reset back in 2010. As a company, we all have to have a phenotypic drug discovery mindset, which means that we have to be prepared for any target, or working on an unknown target, that acts through any compartment (liver, CNS, etc), that modulates physiological endpoints for any disease. I’m no longer a target-based medicinal chemist working on metabolic diseases, I’m a phenotypic drug discovery scientist working on circadian modulators that are disease agnostic. It’s an exciting, challenging and hugely rewarding part of my career and I am relishing working with the Reset team to create a new path for drug discovery in this novel scientific area.
What is Reset Therapeutics’ end goal? I’m thinking about both the modest shorter term goals, and the BHAGs (Big Hairy Audacious Goals) longer term?
Our initial goal was to take the founders'/SAB members' technologies and industrialize them. We realize not all academic science is reproducible in an industrial setting, so this was an important initial goal. Following that, we really had to get the Proof of Concept (POC) that a circadian rhythm platform could generate small molecule modifiers that treat disease in a preclinical animal model. In 4Q13 we managed to utilize a Cryptochrome modulator to ameliorate the symptoms of type 2 diabetes in four different rodent models. In parallel, one of our founders also published on the link between Cryptochrome and Glucocorticoid Receptor and so we were also excited to recently get POC in an animal model of Cushing’s Syndrome (an orphan disease with a large unmet medical need).
Going forward, we expect to utilize the platform to generate multiple small molecule rhythms modifiers against novel circadian targets (similar to how Epizyme is executing on its epigenetic platform). As the literature implicating clock targets and rhythmic dysregulation in various diseases continues to expand, our longer term goal is to be able to “hit top gear” with the platform and bring multiple circadian therapies into the clinic.
I think our BHAG goal is to find multiple partners in order to work on both peripheral and central circadian mechanisms. A long list of diseases are linked to circadian desynchrony (a reciprocal relationship), and we would love to discover small molecule compounds that “normalize” the circadian rhythms in the body in order to resynchronize back to normal. This type of therapy should prove to be maximally efficacious with minimal side effects for multiple diseases.
What are your plans to accomplish these goals, and how does CDD Vault fit in?
In order to accomplish the above goals we really need to build out our in-vitro biology group, in order to be able to deconvolve the targets for multiple phenotypic compounds all in parallel. Once the targets have been deconvolved, that group will also generate primary and secondary assays linking the small molecule phenotype and target various aspects of the disease of interest, particularly as this relates to rhythmic irregularities associated with the disease. This is obviously time and labor intensive.
CDD Vault fits into our plans as the key central data hub for Reset. Every phenotypic compound potentially blooms into its own project. Using CDD to separate all this data into distinct areas with different privileges for the various parties involved will be key in executing on these projects in an efficient manner.
How do you use CDD Vault? And why?
Apart from what was mentioned earlier, the way we use the CDD Vault for the BPN project is the best example of CDD’s strengths. The Orexin Narcolepsy project is funded by the NIH BPN grant and this involves multiple geographically distinct people collaborating on the science. Reset performs all in-vitro and in-vivo biology experiments, AMRI performs all chemistry and in-vitro ADME and Southern Research/SRI perform all in-vivo PK. Added to that, you also have NIH employees and NIH consultants and all of these groups are located in different places across the US. Having a Vault where multiple people can upload, share, and discuss data is essential! CDD, in conjunction with Sharepoint, allows the design team to analyze data, share ideas and make crisp decisions every two weeks – a reasonable time frame for a cycle of synthesis, screening and design. Gone are the days of manually updating Excel spreadsheets and sending via e-mail... thankfully!
What have you liked about working with CDD? What's been good and what could go better in the future?
CDD is as collaborative as its software! I am constantly being asked for feedback and potential new features that I’d like to see added (both short and long term). I like the ability to view dose response curves within SAR tables. I like the ability to be able to segregate projects and share data with different parties for different projects. I like how user friendly, and customizable it is, meaning scientists can spend time doing science and not uploading/curating data. I like the fact that there are multiple updates happening on a regular basis rather than waiting long periods of time for these large updates. Barry, Kellan, Sylvia, and Anna have been tremendous customer-facing employees that constantly fix problems and offer solutions in a professional and efficient manner. They understand our business and understand that time is of the essence for us to be able to bring novel therapies to patients that are desperately in need of help. I know there are numerous CDD employees whose names I don’t know, but I recognize them by speaking so highly of the software.
Keep up the excellent and hard work!
There are a few things that I'd like to see added to the CDD Vault in the future:
- Ability to generate user-defined formulas to be able to generate columns for selectivity, LipE, etc.
- Ability to be able to view data in formats other than SAR tables so that I can do everything in the CDD Vault that currently requires multiple different software.
- Generate virtual compounds and view them in SAR tables next to real compounds.
What was the most memorable interaction you've had w/ another brilliant scientist? And why?
I’ve had many memorable interactions with brilliant scientists, but I’ve always found the most rewarding interactions to be in a group setting where I was part of a highly productive team. They tend to be teams that are not too big and not too small and are made up of open-minded, positive and collaborative people. Everybody feeds off each other to improve upon each other’s ideas and produces high quality science occurring at a rapid pace.
Talk about an “ah-ha” moment in science during your career?
I’ve had a few “ah-ha” moments while working on Pfizer projects, but I think the biggest one was after joining Reset. Once I understood circadian rhythms, and how it affects even target-based drug discovery, I looked back at my big pharma career and wished I’d considered circadian science when (i) considering metabolism of my compounds; (ii) dosing my compounds (chronopharmacology); and (iii) whether my target was expressed differentially over 24 hrs and if it affected other downstream targets in a circadian manner.
Outside of your own research (it can be a competitor or an unrelated group), what is the most fascinating development or study you've recently seen (ideally something that would be broadly of interest to the researcher community)?
Sticking to things that are of interest to Reset, I think there are two key areas that are big for us:
(i) The vaccine safety surveillance system effectively detected an increased prevalence of narcolepsy in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine (Pandemrix). The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. This is an unfortunate adverse event affecting a large number of people across Europe and increasing the prevalence of this debilitating disease.
(ii) Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. The literature in this area has exploded over the last 5 yrs to the point where we cannot ignore the link between rhythms and disease in drug discovery any more. For a recent review see: Gamble, K. L. et al. Crit. Rev. Biochem. Mol. Biol. 2013, 48, 317.
This blog is authored by members of the CDD Vault community. CDD Vault is a hosted drug discovery informatics platform that securely manages both private and external biological and chemical data. It provides core functionality including chemical registration, structure activity relationship, chemical inventory, and electronic lab notebook capabilities!
CDD Vault: Drug Discovery Informatics your whole project team will embrace!