Second Annual

Blood-Brain Penetrant Inhibitors

Discovery and Design of Selective and Potent Inhibitors Crossing the Blood-Brain Barrier

April 24-25, 2017 | Sheraton San Diego Hotel & Marina

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.

Cambridge Healthtech Institute’s Second Annual Blood-Brain Penetrant Inhibitors conference 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

Monday, April 24

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

William F. Elmquist, Pharm.D., Ph.D., Professor and Head, Department of Pharmaceutics; Director, Brain Barriers Research Center, University of Minnesota

8:10 BBB – Brain Tumor Interactions: A Complex, Dynamic System Influencing Efficacy and Resistance

William_ElmquistWilliam F. Elmquist, Pharm.D., Ph.D., 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.

8:40 Small Molecule Kinase Inhibitors for Brain Cancer: Limitations, Challenges and Opportunities

Timothy_HeffronTimothy P. Heffron, Ph.D., Senior Scientist, Discovery Chemistry, Genentech, Inc.

In addition to each of the factors that affect the identification of a successful oncology drug candidate, 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.

9:10 Prediction of Drug Efficiency: Aptuit’s Experience in CNS Drug Design & Discovery

Alfonso Pozzan, Ph.D., Manager & Principal Scientific Investigator, Computational Chemistry, Aptuit

The selection of high-quality drug candidates is recognized as the most important decision in Drug Discovery. In ‘97, Lipinski paved the way towards a more rational use of physicochemical descriptors to predict the quality of such molecules. As an evolution of this concept, we have introduced in 2010 an in vitro/in vivo Drug Efficiency (Deff) coefficient and now an in silico Deff predictor to be used during the Drug Design phase.

9:40 Coffee Break

10:05 Discovery and Synthesis of the Macrocyclic EML4-ALK Inhibitor, Lorlatinib (PF-06463922)

Paul_RichardsonPaul Richardson, Ph.D., 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.

10:35Structure-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, Ph.D., 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. Using rational structure-based design, MSC2120352 was subsequently optimized to a highly potent, kinase-selective, CNS penetrant p70S6K/Akt inhibitor M2698.

11:05 Late Breaking Presentation

11:20Enjoy Lunch on Your Own



1:15 Chairperson’s Remarks

Edward Holson, Ph.D., CSO, KDAc Therapeutics

1:20 Brain Penetrant HDAC Inhibitors to Treat CNS Disorders

Ed_HolsonEdward Holson, Ph.D., CSO, KDAc Therapeutics

1:50 Art and Science of CNS Drug Design

Zoran 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, importance of modern CNS pharmacokinetic concepts including the “free drug” hypothesis, are also discussed.

2:20 Addressing the Inflammatory Aspects of Amyloidosis Using CNS Penetrant p38 Kinase Inhibitors

Michael_BurnetMichael Burnet, Ph.D., Managing Director, Synovo GmbH

We screened appropriate inhibitor sets for CNS penetration in a murine amyloidosis model (APPPS) to select appropriate compounds for study. The centrally available p38 inhibitors reversed this phenomenon providing treated animals with a similar life expectancy to non-diabetic littermates. The substances had no effect on diabetic parameters, and given that the amyloid deposition is largely central in this model, we are investigating the CNS component of this effect. These data suggest that centrally active p38 inhibitors have the potential to treat dementias complicated by Type II diabetes.

2:50 Strategy and Tactics for the Discovery of Kinase Inhibitors: A Lundbeck Perspective

Klaus Baek Simonsen, Ph.D., 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 form two active programs including LRRK2.

3:20Late Breaking Presentation

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


PROTACs: Inducing Protein Degradation as a Therapeutic Strategy

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an “event-driven” paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 Close of Day

Tuesday, April 25

7:30 am Continental Breakfast Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic: Changes in the BBB that Impact Brain Tumor Treatment

Moderator: William F. Elmquist, Pharm.D., Ph.D., Professor and Head, Department of Pharmaceutics; Director, Brain Barriers Research Center, University of Minnesota

  • How does the BBB change as a brain tumor progresses?
  • How does radiation therapy influence the BBB in and around brain tumors?
  • What are the latest imaging techniques for brain tumor diagnosis and treatment?
  • Topic: The Nitty-Gritty of CNS Drug Discovery

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

  • A typical CNS project workflow, challenges and solutions
  • Key parameters, assays and data interpretation
  • Brain delivery systems?
  • Active transport at the BBB
  • PET ligand design
  • Topic: 3D vs. 2D In Vitro Systems - What Are the Benefits vs. Drawbacks of Each?

    Moderator: James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

  • What is the advantage of anatomy vs. function?
  • How does cost figure into this?
  • How does this effect organ integration?


    8:30 Chairperson’s Remarks

    Matt Lucas, Ph.D., Director, Medicinal Chemistry, Yumanity Therapeutics

    8:35 Yeast-Based Phenotypic Screening to Identify Brain Penetrant Inhibitors

    Matt_LucasMatt Lucas, Ph.D., 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.

    9:05 A Human-Analog Platform for the Study of Drug Effects on the CNS and PNS across the Blood-Brain Barrier

    james_HickmanJames J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, 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.

    TCG Life Sceinces9:35 Coffee Break in the Exhibit Hall with Poster Viewing


    10:30 Intact BBB vs. Disease-Altered BBB in ALS

    Svitlana Garbuzova-Davis, Ph.D., D.Sc., Professor, Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida

    My laboratory is focused on translational research examining the therapeutic effects of transplanting human umbilical cord blood in mouse models of ALS and Sanfilippo Syndrome. One current focus of mine is deciphering the mechanisms of the blood-CNS barrier damage in ALS and stroke and engendering barrier repair to restore neurovascular unit functionality in patients with these or other neurovascular diseases.

    11:00 Therapeutic Targeting of Oxygen-Sensing Prolyl Hydroxylases Abrogates ATF4-Dependent Neuronal Death and Improves Outcomes after Brain Hemorrhage in Several Rodent Models

    Rajiv R. Ratan, M.D., Ph.D., Director, Laboratory for Redox Biology and Neural Protection and Repair Burke Medical Research Institute; Professor, Neurology and Neuroscience, Brain and Mind Research Institute, Weill Cornell Medicine

    Protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

    11:30 Understanding the Biology of the Central Nervous System (CNS) Barriers under Homeostatic and Inflammatory Conditions

    Jorge_AlvarezJorge Iván Alvarez, Ph.D., Assistant Professor of Pathobiology, University of Pennsylvania

    Research in the Alvarez lab is aiming to understand the biology of the Central Nervous System (CNS) barriers under homeostatic and inflammatory conditions. These barriers selectively restrict the molecular and cellular trafficking between the periphery and the CNS, but also serve as a signaling interface that actively regulates exchanges between both compartments. They are composed of the blood-brain barrier (BBB), the blood-meningeal barrier (BMB) and the blood-cerebrospinal fluid barrier (BCB).

    12:00 pm Close of Conference