Cambridge Healthtech Institute’s 4th Annual

Blood-Brain Barrier and CNS Drug Discovery

Strategies and Tools to Address Hurdles in CNS Drug Discovery

April 12, 2019 | Hard Rock Hotel | San Diego, California

The blood-brain barrier (BBB) plays a critical role in brain homeostasis – a function it does so well that scientists and drug developers continue to grapple with the challenges of delivering drugs into the brain to treat devastating and life-threatening diseases such as brain cancer and neurodegenerative disorders. As we understand more about the state of the BBB in a healthy and a disease-challenged brain, novel strategies, methods and tools are developed to design and study brain-penetrant molecules. Cambridge Healthtech Institute’s 4th Annual Blood-Brain Barrier and CNS Drug Discovery symposium will once again bring together drug discovery experts to discuss advances in the CNS drug discovery, including the progress towards designing brain-penetrant molecules and emerging drug delivery approaches.

Final Agenda

Friday, April 12

7:30 am Registration Open and Morning Coffee


7:55 Welcome and Opening Remarks

Kaitlin Kelleher, Conference Director, Cambridge Healthtech Institute

Zoran Rankovic, PhD, Director, Chemistry Centers, Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital

8:00 FEATURED PRESENTATION: The BBB and Its Effect on Drug Delivery in Different Disease States

Quentin Smith, PhD, Senior Vice President, Research, Texas Tech University Health Sciences Center


8:30 How Does the Basement Membrane Regulate BBB Integrity in Physiological and Pathological Conditions?

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

Although the blood brain barrier (BBB) attracts lots of attention, most research focuses on its cellular constituents, leaving its non-cellular component - the basement membrane (BM) - understudied. Recent studies show that the BM not only actively regulates BBB integrity, it also serves as the rate-limiting step in inflammatory cell extravasation. In this talk, I will discuss the biological function of the BM in BBB maintenance under both physiological and pathological conditions.

9:00 Networking Coffee Break

9:30 Fibrinogen in Neurological Diseases: Mechanisms, Imaging, Therapeutics

Akassoglou_KaterinaKaterina Akassoglou, PhD, Senior Investigator/Professor, Department of Neurology, Gladstone Institutes/University of California, San Francisco

Recent research has uncovered pleiotropic roles for fibrinogen in neuroinflammation, neurodegeneration, and inhibition of repair. Fibrin-targeting immunotherapy inhibits autoimmunity- and amyloid-driven neurotoxicity in animal models of multiple sclerosis and Alzheimer’s disease, suggesting selective fibrin targeting might be beneficial for suppressing vascular-driven neurodegeneration.

10:00 BBB Organoids: A Next Generation in vitro Drug Screening Platform

Cho_Choi-FongChoi-Fong Cho, PhD, Instructor, Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School

Techniques to model the BBB in vitro are crucial tools to help predict brain uptake of drug candidates prior to in vivo studies. We describe here the utility of 3D multicellular BBB spheroids made of human brain endothelial cells (ECs), pericytes and astrocytes as a screening tool for brain-penetrating agents.

10:30 Theory and Practice of CNS Drug Design

Rakovic_ZoranZoran Rankovic, PhD, Director, Chemistry Centers, Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital

Designing molecules that can overcome the blood-brain barrier and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Here we report experimental data analysis and case studies to illustrate the modern CNS pharmacokinetic concepts, drug discovery workflows and medicinal chemistry strategies for designing molecules with optimal brain exposure.

11:00 Enjoy Lunch on Your Own


1:00pm Chairperson’s Remarks

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

1:05 The Atypical Regulation of GPCR Induced Inflammation and Vascular Leakage

Grimsey NeilNeil Grimsey PhD, Assistant Professor, Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens

GPCR induced proinflammatory signaling is key to the breakdown of endothelial barrier integrity. Our work has identified a conserved atypical pathway for the induction of p38 MAPK signaling.  Which is induced independent from the classical three tire kinase cascade and the activation of MKK3/6. Very little is understood as to how this pathway is regulated. Thus, providing a novel therapeutic target to specifically block proinflammatory GPCR signaling in the vasculature.  


1:35 Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

Mergott_DustinDustin Mergott, Director, Investigative Drug Disposition, Lilly Research Laboratories, Eli Lilly

Co-authors: James E. Audia, Mario Barberis, James P. Beck, Leonard N. Boggs, Robert D. Boyer, Richard A. Brier, Anthony R. Borders, Leslie L. Daugherty, Robert A. Dean, , Larry Ereshefsky, Jon A. Erickson, Pablo Garcia-Losada, Hakop Gevorkyan, Steven J. Green, Erik J. Hembre, Michael C. Irizarry, Douglas E. James, Stanford Jhee, Qun Lin, Jose E. Lopez, Albert Lo, Stephen L. Lowe, Brian M. Mathes, Patrick C. May, David L. McKinzie, Scott A. Monk, Masako Nakano, Warren J. Porter, Zoran Rankovic, Yuan Shi, Stephanie L. Stout, David E. Timm, Brian M. Watson, Brian A. Willis, Leonard L. Winneroski, Zhixiang Yang, Jennifer A. Zimmer

Cerebral deposition of amyloid-β peptide (Aβ) plays a critical role in Alzheimer’s disease (AD) pathogenesis. Owing to its role in the generation of Aβ, the BACE1 enzyme has been a prime target for designing drugs to prevent or treat AD. However, BACE1 has proven to be an exceedingly challenging target for drug discovery, especially due to the requirement for CNS penetration. This presentation will describe the discovery of LY3202626, a low-dose, CNS-penetrant BACE inhibitor capable of reducing CSF Aβ by > 90%.

2:05 Speaker Q&A

2:35 Networking Refreshment Break

3:05 A Roadmap for PI3Kγ Selectivity Design: Discovery of Orally Bioavailable, CNS-Penetrant PI3Kγ Inhibitors with Potential for the Treatment of Multiple Sclerosis

Collier_PhilipPhilip Collier, PhD, Senior Research Scientist, Medicinal Chemistry, Vertex Pharmaceuticals, Inc.

We describe the evolution of a reported pan-PI3K inhibitor into a family of potent and selective inhibitors. Guided by structural data, our scaffold design strategy resulted in compounds devoid of efflux liabilities. Further optimization led to the discovery of a CNS-penetrant, orally bioavailable compound that showed efficacy in a preclinical model of MS.

3:35 Optimization of a Phenotypic Screening Hit in Yeast and the Identification of a Novel Target with the Potential to Treat Parkinson’s Disease

Lucas_MatthewMatthew Lucas, PhD, Senior Director of Chemistry, Medicinal Chemistry, Yumanity Therapeutics

The discovery, design, and phenotype-led optimization of the scaffold that resulted in the discovery of a novel target that plays an important and previously unrecognized role in the neurotoxicity caused by a-synuclein will be described. The a-Synuclein protein is a major driver of Parkinson’s disease and related neurodegenerative disorders. Misfolding and aggregation of a-synuclein triggers a cascade of events, ultimately resulting in neurotoxicity.

4:05 A Versatile and Modular Targeted Nanoparticle Platform for Delivery of Combination Therapies to Adult and Pediatric CNS Tumors

Lam_FredFred Chiu-lai Lam, MD, PhD, Research Scientist, Biology, Koch Institute for Integrative Cancer Research at MIT

We developed transferrin-functionalized nanoparticles (Tf-NPs) that can deliver combination therapies across the BBB to CNS tumors. Treatment of GBM mouse models with drug-loaded Tf-NPs enhances survival and decreases systemic drug toxicities, demonstrating the potential of this nanoscale platform for treatment of CNS tumors.

4:35 Close of Conference