Cambridge Healthtech Institute’s 3rd Annual

Blood-Brain Penetrant Inhibitors

Tools, Strategies, and Design of Brain Penetrant Inhibitors

April 6, 2018 | Hilton Bayfront | San Diego, California

The blood-brain barrier (BBB), while serving a critical role in brain homeostasis, also significantly impedes the penetration of most small molecule inhibitors. Recently, our understanding of the disease-challenged brain barrier has revealed that the BBB itself becomes altered, further affecting the success of drug delivery. With growing interest in developing selective and potent inhibitors for the treatment of brain tumors and CNS diseases, there is an urgent need to understand and overcome the challenging aspect of crossing the BBB. Therefore, designing new small molecules utilizing structural and functional knowledge of the BBB, and how it changes during disease, is becoming essential for the successful development of brain penetrant inhibitors. Cambridge Healthtech Institute’s 3rd Annual Blood-Brain Penetrant Inhibitors symposium will once again convene drug discovery experts to discuss advances in our understanding of the BBB, discuss the discovery and development of selective and potent brain penetrant inhibitors, as well as current and emerging approaches for crossing the blood-brain barrier.

Final Agenda

Friday, April 6

7:25 am Registration and Morning Coffee


7:55 Welcome and Opening Remarks

William F. Elmquist, PharmD, PhD, Professor and Head, Department of Pharmaceutics; Director, Brain Barriers Research Center, University of Minnesota

8:00 Brain Tumor Interactions: A Complex, Dynamic System Influencing Efficacy and Resistance

William_ElmquistWilliam F. Elmquist, PharmD, PhD, Professor and Head, Department of Pharmaceutics; Director, Brain Barriers Research Center, University of Minnesota

This talk will focus on the issues surrounding effective drug delivery to the invasive cells in brain tumors, both primary and metastatic. While molecularly targeted anti-cancer agents have impressive inhibitory action against signaling pathways that drive tumor growth, they have been ineffective in treating brain tumors. The mechanisms responsible for this failure must be explored before progress can be made, and inadequate drug delivery across an intact BBB is one critical factor for primary tumors and micro-metastases in the brain.

8:30 Roche Delivery Platforms for Biotherapeutics to Treat Brain Tumors

Eduard_UrichEduard Urich, PhD, Pre-Clinical Project Leader and Senior Scientist, Roche Pharmaceutical Research and Early Development, NORD Discovery & Translational Area, Roche

I will describe an overview of our recent novel antibody engineering platforms, including our Brain Shuttle technology that utilizes receptor-mediated transcytosis to cross an intact BBB. Experimental data will illustrate the absolute requirement to cross the BBB to remove tumor cells within the brain parenchyma.

9:00 Coffee Break


9:30 POSTER PRESENTATION: Overcoming the Blood Brain Barrier with Focused Ultrasound and Gold Nanoparticles

Carlyn Figueiredo MSc, MD/PhD Candidate, Labatt Brain Tumour Research Centre, The Hospital for Sick Children, University of Toronto

We demonstrate in vivo that only GNP-Cis greatly reduced the growth of tumours and had an overall smaller tumour area as compared to mice receiving cisplatin only. MRI analysis showed that MRgFUS led to increased BBB permeability significantly enhances the accumulation of Cisplatin within the GBM tumour. Furthermore, MRgFUS allows GNP-Cis to extravasate to the boundaries of the tumour and travel a further distance away from blood vessels. Conclusion. Our studies suggest that GNP-Cis conjugates have greater efficacy in inhibiting GBM tumours in vivo, and MRgFUS can be used to focally to enhance the delivery of targeted chemotherapeutics to brain tumours. This study is in congruence with a number of others in the field of focused ultrasound research, highlighting the immense potential of incorporating this technology into the treatment plan for brain tumour patients..

10:00 Discovery and Synthesis of the Macrocyclic EML4-ALK Inhibitor, Lorlatinib (PF-06463922)

Paul_RichardsonPaul Richardson, PhD, Director, Process and Analytical Technologies, Oncology Medicinal Chemistry, Pfizer

This talk will center on the design of PF-06463922, focusing on the optimization of the properties to achieve brain penetration. In addition, the synthesis of PF-06463922 will be discussed with the key step herein being the ring closure to form the final 12-membered macrocycle. The development, optimization and subsequent scale-up of a novel direct arylation route to achieve this will be presented, leading to a sequence that is three steps shorter and is expected to provide a higher overall throughput of the desired API.

10:30 Discovery of Selective Orexin-1 Receptor Antagonists

Terry Lebold, PhD, Senior Scientist, Neuroscience Chemistry, Janssen Research & Development

Presented here will be the discovery, synthetic methods and SAR associated with novel selective orexin-1 receptor antagonists and their evaluation in preclinical models of panic, anxiety and addiction. In addition, we will highlight our first candidate for pre-clinical development, JNJ-54717793.

11:15 Enjoy Lunch on Your Own

12:00 pm Session Break


1:00 Chairperson’s Remarks

Zoran Rankovic, Director, CBT Chemistry Centers, St. Jude Children’s Research Hospital

1:05 Art and Science of CNS Drug Design

Zoran_RankovicZoran Rankovic, Director, CBT Chemistry Centers, St. Jude Children’s Research Hospital

This presentation focuses on the interplay between the physicochemical and CNS pharmacokinetic parameters, and medicinal chemistry strategies towards molecules with optimal brain exposure. Since the challenge of CNS drug discovery could be effectively addressed only with an in-depth understanding of the structure-brain exposure relationships built on reliable and meaningful pharmacokinetic data, the importance of modern CNS pharmacokinetic concepts including the “free drug” hypothesis are also discussed.

1:35 Yeast-Based Phenotypic Screening to Identify Brain Penetrant Inhibitors

Matt_LucasMatt Lucas, PhD, Director, Medicinal Chemistry, Yumanity Therapeutics

Phenotypic screening has undergone a revival in the last decade. In this presentation, I will share some of our learnings from Yumanity’s phenotypic screening platform to bias towards the identification of scaffolds that are brain penetrant with potential utility to treat protein misfolding diseases.

2:05 Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Development of Casein Kinase 1d Inhibitors That Lead To Inhibition of Tau Phosphorylation at Ser202 and Ser396

Jayalakshmi_SridharJayalakshmi Sridhar, PhD., Assistant Professor, Chemistry, Xavier University

Several protein kinases play an important in the progression of neurodegenerative disorders such as Alzheimer's disease. Many of these are targets for potential therapeutics. Our research group has found one such target as Casein kinase 1delta which phosphorylates the tau protein leading to neuro-fibrillary tangles that is a hallmark of Alzheimer's disease.

2:35 Networking and Discussion Session

3:05 Refreshment Break


3:35 Laminin Actively Regulates Blood Brain Barrier Integrity

Yao_YaoYao Yao, PhD, Assistant Professor, Pharmaceutical and Biomedical Sciences, University of Georgia

Laminin, a large family of trimeric proteins, is the only component required for the formation of the basement membrane (BM)---the non-cellular component of the blood brain barrier (BBB). It has been shown that different cells synthesize distinct laminin isoforms at the BBB. Using conditional knockout mutants, we reported that loss of astrocytic laminin leads to BBB disruption and intracerebral hemorrhage, whereas ablation of pericytic laminin results in a much milder BBB breakdown phenotype. These results suggest that laminin/BM also contributes to the maintenance of BBB integrity, and may be targeted for drug delivery to the CNS.

4:05 Serial Cerebrospinal Fluid Collection in Early Clinical Development May Provide Pharmacokinetic and Pharmacodynamic Insights for CNS Drugs

Stanford_JheeStanford Jhee, PharmD, Corporate Vice President, Scientific Affairs, PAREXEL International

One of the main objectives of CNS Phase I clinical development is determination of CNS penetration and its pharmacokinetic and pharmacodynamics profiles. This can be compared to that of preclinical and plasma levels. An indwelling catheter in the lumbar region can provide a safe and tolerable method to collect serial CSF in humans. Such data is a valuable translational information that can be directly be applied to early clinical drug development. Our methods and experience over the last 15 years will be presented with selected data presented.

4:35 T-Type Calcium Channel Blockers for the Treatment of Generalized Epilepsies

Olivier_BezençonOlivier Bezençon, Senior Group Leader, Chemistry, Idorsia Pharmaceuticals Ltd

The discovery and optimization of new, brain-penetrant T-type calcium channel blockers are presented. Optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy are discovered. Along the fine optimization (target potency, brain penetration, and solubility), an Ames negative aminopyrazole as putative metabolite of this compound series was successfully identified. These efforts culminated in the selection of a compound that was elected as a clinical candidate.

5:05 End of Conference