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 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

Kip Harry, Senior Director, Conferences, Cambridge Healthtech Institute

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 Small Molecule Kinase Inhibitors for Brain Cancer: Limitations, Challenges and Opportunities

Timothy_HeffronTimothy P. Heffron, PhD, Senior Scientist, Discovery Chemistry, Genentech, Inc.

Drug discovery aimed at treating neurological cancers must also consider the presence of the blood-brain barrier (BBB). High expression of transporters at the BBB limits most kinase inhibitors from freely reaching CNS malignancies within the brain.This talk will discuss the unmet need for neuro-oncology treatments, the significant opportunities that remain for new kinase inhibitors in this space and the unique challenges and considerations for brain penetrant kinase inhibitor programs.

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 Structure-Based Optimization of a Potent, Selective and CNS Penetrable p70S6K/AKT Inhibitor M2698 for the Treatment of Tumors with PAM Pathway Genomic Alterations

Igor_MochalkinIgor Mochalkin, PhD, Associate Director, Medicinal Chemistry & Lead Optimization, EMD Serono, Inc.

Herein, we present the successful optimization of the quinazoline-8-carboxamide (QCA) series of dual p70S6K/Akt inhibitors. The initial lead MSC2120352 was identified in a focused, kinase library screen. MSC2120352 binds in the ATP-binding pocket of the kinase: the QCA amide group forms bidentate interactions with the hinge region (Glu173-Leu175); the electron-rich π system of the benzyl binds in the G-loop, utilizing noncovalent cation-π interactions with the catalytic lysine-123.

11:00 Sponsored Presentation (Opportunity Available)

11:15 Luncheon Presentation (Opportunity Available) or 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 Rational Design of Exquisitely Selective Inhibitors of the GSK3 Kinase Isoforms for the Treatment of Psychiatric and Neurological Disorders

Florence Wagner, PhD, Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, The Broad Institute

We report the discovery of the first isoform selective inhibitors of GSK3β or GSK3β. Exploiting a single amino acid difference within the ATP binding domain, we have developed novel, potent, brain penetrant inhibitors with unprecedented kinome selectivity. These isoform selective inhibitors of GSK3β or GSK3β successfully decouple effects on β-catenin, and therefore mitigate oncogenic concerns.

2:35 Networking and Discussion Session

3:05 Refreshment Break


3:35 Lead Optimization of Pyrazole Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12)

Snahel_PatelSnahel Patel, Senior Scientific Manager, Discovery Chemistry, Genentech, Inc.

Neurodegenerative diseases such as Alzheimer's and Parkinson's represent significant unmet medical needs with no therapies able to slow the course of disease. Dual Leucine Zipper Kinase (DLK) is a neuronal specific upstream regulator of the JNK pathway that was recently identified as a central regulator of degeneration in multiple contexts. We have progressed lead optimization of a pyrazole scaffold towards a desirable profile for a small molecule therapeutic and demonstrating activity in neurodegeneration models.

4:05 Strategy and Tactics for the Discovery of Kinase Inhibitors: A Lundbeck Perspective

Klaus_Baek_SimonsenKlaus Baek Simonsen, PhD, Vice President, Discovery Chemistry, DMPK and Molecular Screening, Lundbeck

This talk will highlight our drug discovery philosophy and strategies towards the discovery of new CNS drugs for kinases. The various challenges within drug discovery in general and CNS in particular will be discussed together with contemporary understanding of drug discovery and medicinal chemistry scholarship, translatability and project execution for this target class. Our strategy and search for novel kinase inhibitors will be illustrated with examples from two active programs including LRRK2.

4:35 A Human-Analog Platform for the Study of Drug Effects on the CNS and PNS across the Blood-Brain Barrier

James_HickmanJames J. Hickman, PhD, Professor, Nanoscience Technology, Chemistry, Biomolecular Science, University of Central Florida

In this system, the BBB consists of human stem cell-derived endothelial cells and astrocytes on opposing sides of a thin carbon-based membrane. The neuronal cultures represent the central nervous system with hippocampal neurons or the peripheral nervous system with motoneurons. The setup allows for the continuous monitoring of the trans-endothelial electrical resistance as well as the recording of neuronal activity in response to compounds or compound combinations.

5:05 End of Conference

* The program is subject to change without notice, due to unforeseen reason.