Drug Discovery 2019

AI is transforming drug discovery and development (3D) including clinical trials by increasing efficiencies, decreasing the gap between data and our ability to utilize data and most importantly making this journey patient centric. Non-invasive and non-intrusive animal and patient monitoring technologies lead and continue to lead development of novel digital biomarkers. Incorporation of digital endpoints and computational technologies into nonclinical and clinical trials leads to earlier and objective detection of physiological and behavioral changes, including off-target effects that lead to earlier decisions thereby reducing animal and patient burden. Leveraging recent advances in high-throughput technologies and machine learning provides an opportunity for more precise and more efficient target identification process. This talk will discuss these technologies and present their impact through case studies within clinical and nonclinical phases of 3D.

Second harmonic generation (SHG) is a biophysical method that sensitively measures real-time conformational change of biomolecules attached to membranes. SHG has recently been applied to detect protein conformational changes in the presence of biological ligands and small molecules. I will describe implementation of SHG as a primary screening platform to identify novel fragment ligands to oncogenic KRas. KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a novel fragment binder to KRasG12D and then used 1H 15N HSQC NMR to characterize its binding site as a pocket adjacent to the Switch II region. The unique sensitivity of SHG furthered our study by revealing distinct conformations induced by our hit fragment compared to DCAI, a Ras ligand previously described to bind the same pocket, identified by fragment based NMR screening. This study highlights SHG as a high-throughput screening platform that reveals structural insights in addition to ligand binding.

Learning Objectives: 

1. Ras proteins, once considered “undruggable”, are now being subjected to a variety of new chemical and biophysical techniques to identify potential drugs that bins to shallow pockets in the protein
2. The biophysical phenomenon referred to as second harmonic generation (SHG) can be used as a tool for discovering molecules that bind to proteins of interest

Multiplexing IHC is a technique that is increasing in demand as more and more researchers and physicians are being tasked with doing more with less. With multiplexing, you have the advantage to view different targets and their levels of expression in relation to one another. In this presentation, we will review the different technologies and techniques that are currently available to assist with developing a multiplex assay. After a brief overview of the technologies, we will apply some of those technologies and walk through an example of optimizing a multiplex assay. Although digital analysis of multiplexed slides can be an important factor in the interpretation of a multiplexed assay, this presentation will focus on and emphasize the staining aspects of the assay optimization.

Learning Objectives: 

1. Understand the utility and methods for multiplexing
2. Understand the principles behind multiplex assay development

Too frequently the investigator will provide “scientific” reasons to justify precluding analgesics from experimental procedures that may involve more than momentary pain, often with solid literature citations.  What is too frequently dismissed is the fact that unalleviated pain itself constitutes an uncontrollable experimental variable that may, in many cases, be more impactful than the effect that analgesics could have in the experimental results.  Yes, analgesics may alter immune function as well as certain molecular pathways.  However, pain also alters immune function and has a profound influence on the hypothalamic-pituitary-adrenal axis and therefore the animal’s overall physiology.

Through this presentation, Dr. Perret-Gentil will demonstrate the effect that unmitigated pain may have on research, and by doing so, he hopes to persuade the scientific community to give the issue of pain and analgesics greater consideration before dismissing their use within their study design.  Practical suggestions will be presented for effective control of both physical and mental pain (distress).

Learning Objectives: 

1. Demonstrate the effect that unmitigated pain may have on research outcomes. This effect can be more profound than pain-relieving drugs may have on research data 
2. Provide practical suggestion for the minimization of physical and mental pain

Small size, highly selective nature, flexible chemistry and ease of manufacturing make nucleic acid aptamers attractive for multiple applications in human diagnostics and drug discovery.  In this presentation, we will describe the aptamer selection process and describe key challenges that have been overcome to identify aptamers that selectively recognize small molecule targets.  Finally, we will share examples of aptamers used for biomarker discovery, drug delivery, therapy, treatment monitoring, pharmacokinetics/dosing studies, and diagnosis.

Learning Objectives: 

1. Understand the ways in which aptamers can provide advantages over traditional affinity agents in drug discovery and diagnostic product development processes.
2. Learn about healthcare applications of aptamers for small molecule targets and cell surface proteins. 

Dramatic responses observed with targeted agents in the ‘right’ genomic context have fueled large scale sequencing efforts to identify ‘effective’ treatments for a given patient. In order to expeditiously evaluate a targeted agent against a potential ‘driver’ genetic aberration, so-called Basket trials are conducted. Basket trials enroll patients with multiple tumor types that carry a common genetic aberration and evaluate a single targeted treatment regimen. I will discuss the rationale, design, and challenges in conducting Basket trials.

Learning Objectives:

1. Learn about when to consider conducting a Basket trial and how to design it
2. Learn about the promises and challenges of identifying patients based on genomic aberrations
 

Ageing is a complex process that has been observed in all biological systems at every level of organisation. Some anti-ageing interventions have demonstrated life-extending effects in model organisms. However, the translation of these interventions in human clinical practice remains limited due to the absence of comprehensive ageing biomarkers. Recent studies suggest that a set of biomarkers, rather than any individual biomarker, constitute the most effective means of assessing the health status. The presentation will cover the development of comprehensive and robust biomarkers of ageing using deep learning and blood biochemistry, transcriptomics, and even imaging data, to be able to track the effectiveness of the various interventions we are developing.

Learning Objectives: 

1. Different AI Approaches to aging biomarker development
2. How AI can revolutionise aging research and how aging research can accelerate AI research