Brain Penetrant Inhibitors

Discovery and Development of Selective
and Potent Inhibitors Crossing the Blood Brain Barrier

April 22, 2016

Brain Penetrant Inhibitors Track 

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 inaugural Brain Penetrant Inhibitors will 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

8:00 am Registration and Morning Coffee


8:30 Chairperson’s Opening Remarks

Snahel Patel, Scientific Manager, Discovery Chemistry, Genentech, Inc.

8:40 FEATURED PRESENTATION: Small Molecule Permeability across an Intact BBB: Necessary for Effective Treatment of Brain Tumors?

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. Many of the newer, molecularly-targeted anti-cancer agents have impressive inhibitory action against various signaling pathways that drive tumor growth. However, they have been ineffective in treating brain tumors. Molecularly-targeted signal transduction inhibitors are often substrates for active efflux transporters at the BBB, and this delivery-limiting mechanism must be overcome before these inhibitors can be adequately tested in clinical trials.

9:25 NKTR-102 Efficacy Versus Irinotecan in a Mouse Model of Brain Metastases of Breast Cancer

Paul_LockmanPaul Lockman, Ph.D., Professor and Douglas D. Glover Endowed Chair, Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University Health Sciences Center

Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.

9:55 Coffee Break in the Exhibit Hall with Poster Viewing


10:35 Predicting P-Glycoprotein Substrates Using Kriging

Istvan_EnyedyIstvan Enyedy, Ph.D., Senior Scientist, Drug Discovery, Biogen

P-glycoprotein is one of most important transporters involved in stopping compounds from penetrating the blood-brain barrier. Thus, predicting P-glycoprotein mediated efflux is important in the development of therapeutic agents targeting the central nervous system. Data obtained from testing more than 800 in house compounds in MDR1-MDCK permeability assay was used to build a prediction model using Kriging. The performance of full and local Kriging models and the nearest neighbor approach will be presented.

11:05 PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

Ted W. Johnson, Ph.D., Research Fellow, Medicinal Chemistry, Pfizer Oncology

PF-06463922, a novel macrocyclic inhibitor of ALK/ROS1, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutants representing all of the patient crizotinib resistant mutations reported to date. Successful optimization of molecular weight and lipophilic efficiency leveraging structure-based drug design techniques led to ligands with overlapping broad spectrum potency, low transporter efflux, and brain penetration. PF-06463922 is currently in Phase 1/2 clinical trials.

11:35 Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Xiaolin_ZhangCo-Presentation: Xiaolin Zhang, Ph.D., Vice President and Head, Innovation Center China, AstraZeneca

Qingbei Zeng, Ph.D., Principal Scientist, Innovation Center China, AstraZeneca

Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.

12:05 pm Selected Presentation: Brevican-Specific Peptides for the Development of Next-Generation Therapeutics for Glioblastoma

Choi-Fong Cho, Ph.D., Postdoctoral Fellow, Neurosurgery, Brigham and Women's Hospital

12:20 Enjoy Lunch on Your Own


1:35 Chairperson’s Remarks

William M. Pardridge, M.D., Founder and CSO, ArmaGen

1:40 Blood-Brain Barrier Endogenous Transporters as Therapeutic Targets: New Model for Small Molecule CNS Drug Discovery

William_PartridgeWilliam M. Pardridge, M.D., Founder and CSO, ArmaGen

The blood-brain barrier (BBB) limits the uptake of most drugs by brain, and the traditional approach to the BBB problem is the use of medicinal chemistry to increase drug lipid solubility, and increase lipid-mediated transport across the BBB. This presentation advocates a new model to CNS drug discovery of BBB-penetrating small molecules, whereby drug candidates are screened for carrier-mediated transport (CMT) across the BBB.

2:10 Rational Design of Exquisitely Selective Inhibitors of the GSK3 Kinase Isoforms for the Treatment of Psychiatric and Neurological Disorders

Florence_WagnerFlorence Wagner, Ph.D., 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 mitigates oncogenic concerns. These compounds will help to delineate the biological function of each isoforms and for their potential use in a variety of disorders including psychiatric and neurological disorders.

2:40 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.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40 Selected Presentation: Use of Nanoparticles to Cross the Blood Brain Barrier

Hans-Joachim Galla, Ph.D., Biochemistry, Chemical Thermodynamics, University of Münster

4:10 Discovery and Preclinical Profiling of LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease

Paul Galatsis, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer

We will communicate our strategy for designing brain penetrant kinase inhibitors and share medicinal chemistry insights into targeting the key cause of familial Parkinson’s disease, LRRK2. We will provide examples of compounds that have in vivo activity at less than 1 mg/kg oral dosing.

4:40 Close of Symposium