Advances in Drug Discovery and Development

Protein-protein interactions and allosterically regulated enzymes have been challenging but important targets for probe- and drug discovery. We and others have found that fragment-based lead discovery can provide chemical starting points and furthermore serve as insightful probes of protein conformation. The Tethering method of fragment discovery links thiol containing compounds to specific cysteine residues and therefore serves as a site-directed approach to interrogating cryptic allosteric sites and protein interfaces.

I will describe recent advances in computational protein design which allow the generation of new protein structures and functions. I will describe the use of these methods to design ultra-stable idealized proteins, flu neutralizing proteins, high affinity ligand binding proteins, and self assembling protein nano-materials. I will also describe the contributions of the general public to these efforts through the distributed computing project Rosetta@home and the online protein folding and design game FoldIt.

The RNA-guided nuclease Cas9 from the microbial CRISPR adaptive immune system has emerged as an exciting tool for precise genome editing in eukaryotic cells. This presentation will discuss the technical development as well as current and future applications and challenges.

Master regulatory transcription factors localize to the genome in a manner influenced by chromatin accessibility and influencing global chromatin structure. With an interest in understanding chromatin-dependent signal transduction to RNA polymerase in developmental and disease biology, we have undertaken to discover and optimize small molecule modulators of chromatin regulatory factors. These incisive chemical probes have availed new insights into chromatin structure and function, and suggest plausible translational opportunities for the targeted development of drug-like derivatives in cancer and non-malignant indications. Genomewide studies of the effects of chromatin-targeting probes has revealed new structural features of the regulatory human epigenome. Using novel biotechnologies and computational approaches, we can characterize for the first time how and where chromatin-directed drugs interact with the genome. Discussed in this lecture will be mechanistic and translational efforts to modulate gene regulatory pathways of lysine acetylation in cancer transcriptional signaling. Illustrations of how this research has translated to human clinical investigation will be provided, highlighting three first-in-class drug molecules.

At Biogen Idec, we have implemented a 3 part innovation operating model which includes innovation mentoring, agile experimentation and transition of experiments into pilots. In this presentation you will learn how we have developed and implemented this model and applied it successfully from brainstorming events at hackathons that have followed through to projects in a mature technology portfolio.

At Biogen Idec, we have implemented a 3 part innovation operating model which includes innovation mentoring, agile experimentation and transition of experiments into pilots. In this presentation you will learn how we have developed and implemented this model and applied it successfully from brainstorming events at hackathons that have followed through to projects in a mature technology portfolio.

This lecture will provide an overview of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD), focusing on how an Academic Drug Discovery Center was established and is maintained. I will discuss why we elected to focus on allosteric modulation of GPCRs and how we interact with corporate partners (both biotech and big Pharma) and the structure of licensing and sponsored research. Key to the success of the Center is an appreciation that there is no 'one size fits all' for collaborations with industry and biotech, and our Center has thus far formed seven unique collaborations. In this talk, I will discuss all of these, as well as the pros and cons of the different models. Finally, I will showcase an example from HTS to IND-enabling studies for a challenging target with a corporate partner that was successful due to the 'deep dive' into the basic science by our academic arm of the VCNDD.

Professor Stockwell will discuss the discovery of ferroptosis, a novel model of regulated but non-apoptotic cell death. He will describe how some tumors are sensitized to ferroptosis and may be targeted with compounds that inhibit cystine-glutamate exchange or the lipid repair enzyme Gpx4, leading to ferroptotic cell death. In addition, he will discuss small molecule inhibitors of ferroptosis, and how such compounds have been used to implicate activation of ferroptosis in numerous degenerative diseases.

In the past decade, we have witnessed an explosion in the availability of high-resolution structural information that sheds light on the binding of diverse classes of ligands to both soluble proteins and integral membrane receptors. From orthosterics to allosterics, from tiny fragments to enormous rule-breakers, we know more than ever about how ligands bind. However, the ability to accurately predict binding free energies has lagged behind, significantly limiting the utility of this structural information. The good news is that in the past few years there has been a breakthrough in ligand binding free energy prediction. I will summarize the evidence and suggest ways to effectively deploy this new capability

A panel of veteran biotech reporters will discuss hot topics in drug development. Expect a lively debate on emerging technologies, shifting dynamics on drug pricing, and the general health of the industry.

This presentation will focus on NuMediis general approach towards the discovery of new therapeutic uses for existing drugs. While the business models for repurposing marketed drugs versus repositioning of proprietary shelved assets remain distinct, each with their unique opportunities and challenges, much of the underlying big data content and computational approaches used to identify lead assets in a given therapeutic area of interest remain constant. This talk will provide a high level overview of some of the tools we have deployed to identify new uses of existing drugs. A couple of use cases will be presented describing the specific use of chemogenomics and systems biology methodologies to identify new drugs/targets in Inflammatory Bowel Disease and Psoriasis.

Heptares Therapeutics is a structure based drug discovery and development company which uses it StaR technology to enable X-ray structures, fragment screening and other biophysical techniques for G-protein coupled receptors. These methods have been applied to previously undruggable or challenging GPCRs resulting in a pipeline of new candidate medicines for diseases including Alzheimer's disease, schizophrenia and ADHD. This talk will give examples of how structure based methods have been applied across the superfamily of GPCRs.
 

The ever-quickening pace of breathtaking advances in our understanding of disease biology has implicitly promised a profusion of drugs that will dramatically improve human health and well-being. Realization of this promise remains frustratingly elusive. Where are all the new drugs? We contend that a major contributing factor is the limitations in target scope of the two well-establish drug modalities, namely small molecules and protein therapeutics. Addressing this targetability gap will require the discovery and development of entirely new structural classes of drugs and the pioneering of new strategies for finding them. Any fundamentally new class of drug introduces discovery challenges that fall outside the hard-won risk-mitigation paradigms for established classes of drugs, hence the reluctance of pharma, biotech and even the investment community to fully embrace next-generation therapeutic modalties. Learning how to navigate these challenges will therefore fall disproportionately to the academic community, and will not be easy or happen quickly. That said, recent developments in the field of next-generation therapeutics give reason to be cautiously optimistic.

The ever-quickening pace of breathtaking advances in our understanding of disease biology has implicitly promised a profusion of drugs that will dramatically improve human health and well-being. Realization of this promise remains frustratingly elusive. Where are all the new drugs? We contend that a major contributing factor is the limitations in target scope of the two well-establish drug modalities, namely small molecules and protein therapeutics. Addressing this targetability gap will require the discovery and development of entirely new structural classes of drugs and the pioneering of new strategies for finding them. Any fundamentally new class of drug introduces discovery challenges that fall outside the hard-won risk-mitigation paradigms for established classes of drugs, hence the reluctance of pharma, biotech and even the investment community to fully embrace next-generation therapeutic modalties. Learning how to navigate these challenges will therefore fall disproportionately to the academic community, and will not be easy or happen quickly. That said, recent developments in the field of next-generation therapeutics give reason to be cautiously optimistic.

Antibiotics are among the most important advances in the history of modern medicine. They turned often acutely fatal infections into treatable indications with radical cures. Antibiotics continue to enable nearly all of the medical and surgical advances that we turn to as treatments for every human and animal disease. Yet our ability to develop safe and effective antibiotics is out-competed by natural selection as well as increasingly difficult challenges in identifying new, clinically-validatable targets and high value chemical starting points for new therapeutics. Some new strategies and technologies are allowing us to gather a deeper understanding of the biology of microorganisms both pathogens and resident flora as well as means to test chemical hypotheses to guide antibacterial SAR. The time is right and the tools are available or within reach for scientists within all types of organizations to make an enormous collective impact on this challenging field!

Target selection is arguably the most important decision in all drug discovery and development activities. No amount of great science can overcome the selection of the wrong target. The rapid expansion of potential targets for drug discovery as a result of modern genetic sequencing and analysis technologies has made target selection more challenging than ever before. This presentation will address the role of academic research centers in addressing the target selection problem

Diseases caused by an excess of protein function can often be treated by small molecule inhibitors. In contrast, many diseases caused by missing proteins cannot be addressed with this classic therapeutic strategy. Emerging evidence suggests that small molecules may further possess the capacity to autonomously replicate the functions of many missing proteins, thereby operating as prostheses on the molecular scale. A powerful new building block-based approach for small molecule synthesis is facilitating the systematic study of a variety of small molecules with protein-like functions and thereby brightening the prospects of realizing the substantial potential of this molecular prosthetics approach.

Transforming serious brain disease through cutting edge science, generating novel medicines that enable patients to overcome everyday challenges and achieve their full potential

Duchenne Muscular Dystrophy (DMD) is an X-linked genetic disease occurring in 1 in 3,500 births, and is uniformly fatal in boys. It is caused by any one of over 50 known mutations in the gene for dystrophin that result in the production of little to no dystrophin protein a large protein with both structural and signaling capacity that is critical to the normal function of all muscle types. DMD shares many characteristics with other rare diseases that have proven distinctly challenging to drug developers. This presentation will review those issues and illustrate how translational science has, and can, dramatically accelerate the path to potentially life-saving treatments for rare disease patients.

Since leaving Pfizer to go back to academia in 2007, Andrew Hopkins (University of Dundee, UK) has been a leading researcher in the search for new informatics and computational methods to improve the design of effective drug candidates against G-protein coupled receptors and other prominent drug classes. In this presentation, Hopkins reviews his groups latest progress using Bayesian approaches for Algorithmic Drug Design, which show immense promise for the identification of new classes of small molecule drug compounds.

Macrocycles offer a new structural class that has the potential to address challenging protein-protein interaction targets and still present attractive drug-like properties including cell membrane penetration and oral bioavailability. Indeed a number of orally active drugs based on naturally occurring macrocycles provide a compelling precedent for this argument. Ensemble have used DNA-programmed chemistry to make over 10 million synthetic macrocycles in a library format that permits rapid and efficient screening against therapeutically relevant targets. The talk will present successful Ensemble case studies with XIAP antagonists for oncology, and IL17 antagonists for inflammatory disease.