Over the past decade, kinase drug discovery has resulted in the rapid and unparalleled development of a new generation of drugs, with over 25 small molecules currently approved by the FDA. As the rate of approval continues to accelerate, developers have found new ways to expand into a deeper portion of target space within the human kinome, moved beyond cancer and into chronic disease indications, particularly within CNS and cardiovascular disorders, as well as increased interest in allosteric modulation and covalently binding compounds. Although kinase drug discovery has already produced an impressive collection of approved therapies, this field remains one of the most vital and burgeoning arenas for pharmaceutical development.
Cambridge Healthtech Institute’s 7th annual Kinase Inhibitor Chemistry will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase drug discovery.
Wednesday, April 20
12:30 pm Registration
1:30 Chairperson’s Remarks
Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV
1:40 Kinase Inhibition Modalities: The Hydrophobic Spine and the Discovery of Slowness
Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV
Medicinal Chemistry approaches towards the discovery of novel kinase inhibitors has evolved far beyond the traditional type I and type II inhibitors in that protein epitopes on the enzyme surface remote from the ATP binding site have been utilized by small molecule inhibitors. After a brief overview of the heterogeneity of inhibition modes, the concept of the hydrophobic spine will be introduced that can serve as the structural framework for designing low-molecular weight kinase inhibitors. Manipulation of the hydrophobic spine topology causes conformational changes in the catalytic kinase domain, thus offering new opportunities to engineer selectivity, and to optimize binding kinetic attributes. In this presentation the prospective engineering of binding kinetic signatures into inhibitors that exhibit slow k-off by applying “deep-pocket-directed” scaffolds is exemplified. The details of the applied “retro-design” approach for novel kinase inhibitors that disrupt the hydrophobic spine will be highlighted by a lead finding campaign that yielded novel, selective, and highly efficacious CDK-8 inhibitors.
2:10 Selected Presentations:
Structure Guided Inhibitor Design of the Lipid Kinase PI4KB Yields Subnanomolar Inhibitors
Evzen Boura, Ph.D., Group Leader, Structural Biology, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic
Achieving Small-Molecule Induced Disruption of CK2β Dimer Using a Fragments-Based Approach
Wei Guang Seetoh, Research Scientist, Chris Abell's Lab, University of Cambridge
2:40 Focused Mapping for Characterizing Binding Sites and Setting Up Ligand and Structure-Based Methods
Istvan Enyedy, Ph.D., Senior Scientist, Chemical and Molecular Therapeutics, Biogen
Computational solvent mapping was originally developed for identifying “hot spots” on protein surfaces. Our goal was to use this information in order to characterize the binding site and obtain information about features a ligand should have in order to optimally bind to the target. To achieve our goal we are using a set of 19 fragments, and evaluated focused mapping to generate “fake” ligands that capture all interactions a ligand can form with the binding site. Results obtained using ROCS, FRED, HYBRID, and POSIT will be presented.
3:10 Organizing 3D Project Data for Structure-Based Drug Design
Essam Metwally, Ph.D., Senior Scientist, Chemical Computing Group
It is often desirable to organize disparate crystallographic project data into a common homogeneous format, ready to use for modelling. We present a web-based application that permits users to specify numerous options controlling superposition and alignment of structures in a family or project, ligand specification, and whether electron densities or other grids are to be included. The final result is a project database containing superposed structures all in the same frame of reference. From here, structures can be dynamical regrouped, for example by scaffold class, for easy management, and can be easily browsed and used as a starting point for further research. The system is able to handle multi-subunit complexes, including structures which may be missing subunits, by using a novel algorithm to determine which subunits of each complex correspond to each other.
3:40 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Mitochondrial Toxicity of FDA Approved Tyrosine Kinase Inhibitors: Towards Safer New Drugs?
Qiang Shi, Ph.D., Principal Investigator, National Center for Toxicological Research (NCTR), FDA
Six FDA approved tyrosine kinase inhibitors (TKIs) have a Black Box Warning for hepatotoxicity in the product labelling. The mechanism is unknown. We will present data to demonstrate if mitochondrial toxicity can help predict TKI hepatotoxicity. Hepatotoxicity is the most important safety issue that restricts the clinical use of tyrosine kinase inhibitors (TKIs). The development of some TKIs were discontinued due to hepatotoxicity. Our data will provide mechanistic insights into TKI hepatotoxicity and shed light on how to predict and prevent such toxicity in the drug development process.
5:00 An Integrated Approach to the Discovery, Development, and Clinical Use of Novel Kinase Inhibitors for the Treatment of Cancer
Shahrooz Rabizadeh, Ph.D., CSO, Research and Development, NantOmics, LLC; NantBioScience, Inc.
We are taking a multi-pronged approach to the discovery of novel kinase inhibitors by employing a suite of technologies: genomics to discover novel and patient-specific targets, fragment-based chemistry, high-throughput discovery, and molecular modeling to define novel pockets in kinases and refine hits for more specific targeting. Our kinase inhibitors include a compound targeting c-Met that is in phase 2 clinical trial testing; two multi-kinase inhibitors nearing IND submission; and multiple small molecule compounds that specifically target Trk and FGFR.
5:30 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. Check our website in February to see the full listing of breakout topics and moderators.
Emerging Kinase Inhibitor Design Paradigms
Moderator: Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV
- Improving ADME-related and off-target properties
- Improving the correlation between biochemical and cellular or in-vivo efficacy
- Optimizing the residence time of compound-target complexes
Best Practices for the Discovery and Development of Allosteric Modulators
Moderator: Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer
- Rational design approaches for allosteric kinase modulators
- Insights into MOA using structural, biophysical and kinetic studies
- Optimization strategies
Blood Brain Barrier (BBB) Penetration with Kinase Inhibitors
Moderator: Paul Galatsis, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer
- Compound design strategies: physicochemical properties, in silico tools
- Methods for assessing brain penetration: preclinical (Kpuu), clinical (PET tracers), translational biomarkers of central exposure
- Safety issues: minimizing peripheral off-target exposure, selectivity, Ceff
6:15 Close of Day
6:30 Dinner Short Courses*
*Separate registration required
Day 1 | Day 2 | Download Brochure
Thursday, April 21
7:45 am Breakfast Presentation: DNA Encoded Libraries and the Economics of Early Stage Drug Discovery: Managing the Economics of Serendipity
Barry A. Morgan, Ph.D., Visiting Professor, Institute for Molecular Medicine, University of Texas Health Sciences
A review of FDA approved drugs, and the increased cost of drug discovery over the past few decades highlights the unsustainability of the current model for bringing new medicines to clinical practice. We will review the factors involved in this analysis, and present a case for DNA encoded library technology bringing disruptive change to early stage drug discovery.
8:30 PLENARY KEYNOTE PRESENTATION
Cell-Penetrating Miniproteins
Gregory L. Verdine, Ph.D., Professor, Departments of Stem Cell and Regenerative Biology, Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University
It has been estimated that as few as 10-15% of all potential targets are targetable in vivo by either biological or small molecules. To address this deficiency, we and FOG Pharmaceuticals are developing cell-penetrating mini-proteins, molecules that combine the ability of proteins to target large flat surfaces, with the ability of small molecules to penetrate cells. Progress on the development of cell-penetrating mini-proteins will be reviewed in this talk.
9:30 Coffee Break in the Exhibit Hall with Poster Viewing
10:10 Chairperson’s Remarks
10:15 FEATURED PRESENTATION: Tailoring Residence Time Utilizing Reversible Covalent Cysteine Targeting
Michael Bradshaw, Ph.D., Senior Scientist, Principia Biopharma
Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach.
10:45 Oxopyrido[2,3-d]pyrimidinyl Derivatives as Irreversible Epidermal Growth Factor Receptor (EGFR) Inhibitors with Improved Selectivity for the L858R/T790M Mutant Over Wild-Type
Ryan Wurz, Ph.D., Senior Scientist, Medicinal Chemistry, Amgen, Inc.
One of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) is the threonine790−methionine790 (T790M) point mutation of EGFR. The discovery of a series of irreversible EGFR inhibitors selective for the T790M mutant will be described. This led to the discovery of compound 1 which showed promising antitumor activity in a H1975 (EGFR T790M bearing cell line) xenograft model upon p.o. dosing. Formulation in PLGA microspheres and subcutaneous administration resulted in improved efficacy.
11:15 Discovery of Kinase Inhibitor Probes Through Broad Selectivity Profiling
Jeremy Hunt, Director, Screening KINOMEscan, DiscoverX Corporation
Highly selective chemical probes are needed to explore underlying biological function of protein kinases. The SGC recently partnered with DiscoverX to annotate over 600 kinase inhibitors through broad selectivity profiling. Presented here are the resulting data which should facilitate target validation and new drug discovery efforts of understudied kinases.
11:30 Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol
Eric Goedken, Ph.D., Principal Research Scientist, AbbVie Bioresearch Center
The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently inhibit Jak3 activity in cell-based assays.
12:00 pm Targeting JAK3 with Covalent Inhibitors
Chris Burns, Ph.D., Laboratory Head, Chemical Biology Division, Walter and Eliza Hall Institute, Australia
Selective inhibition of JAK3 has promise as treatment for auto-immune and inflammatory diseases because JAK3 expression is limited to cells of the immune system. Other members of the JAK family are widely expressed. Discussion on the optimization of JAK3-targeted agents has been embargoed until this year due to a multi-year collaboration with Novartis. The optimized compounds represent the most selective and potent JAK3 inhibitors reported.
12:30 Enjoy Lunch on Your Own
1:30 Ice Cream Refreshment Break in the Exhibit Hallwith Poster Awards
2:15 Chairperson’s Remarks
Alexandr P. Kornev, Ph.D., Project Scientist, Department of Pharmacology, University of California, San Diego
2:20 Dynamics-Based Allostery in Protein Kinases
Alexandr P. Kornev, Ph.D., Project Scientist, Department of Pharmacology, University of California, San Diego
Active kinases reveal a dynamic pattern with residues clustering into semirigid communities that move in μs-ms timescale. Previously detected hydrophobic spines serve as connectors between communities. Integration of the communities depends on the assembly of the hydrophobic spine and phosphorylation of the activation loop. Single mutations can significantly disrupt the dynamic infrastructure and thereby interfere with long-distance allosteric signaling that propagates throughout the whole molecule.
2:50 Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods
Alexander Dömling, Ph.D., Professor, Drug Design, University of Groningen
The protein kinase PDK1, which lies at the center of the growth-factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells. ANCHOR.QUERY software was used to discover a potent allosteric PDK1 kinase modulator. Using a recently published PDK1 compound as a template, several new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERY approach.
3:20 Refreshment Break
3:40 Allosteric Activators of AMP-Activated Protein Kinase for the Treatment of Diabetic Nephropathy
Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer
AMP-activated protein kinase (AMPK) is a serine/threonine kinase that detects and responds to changes in cellular energy status. In recent years, AMPK has emerged as an attractive target for the treatment of a number of metabolic diseases. Starting from a high-throughput screening hit, we have developed a clinical candidate for diabetic nephropathy through optimization of physico-chemical properties and by computational methods. Furthermore, structural, biophysical and kinetic studies have provided additional insights into the molecular mode of action of our allosteric AMPK activators. I will describe the discovery of our clinical candidate along with in vitro and in vivo data that support its utility for renal diseases.
4:10 Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor
Andreas Marzinzik, Ph.D., Director, Hit Generation Science, Novartis Institutes for BioMedical Research
The hit generation strategy to identify inhibitors targeting allosteric sites will be discussed. It is shown how learnings from allosteric kinase projects like BCR-ABL are transferred to discover and optimize selective PAK inhibitors. PAK is a family of serine-threonine kinases consisting of six isoforms. Most of the PAK isoforms are considered as promising oncology targets, because of their overexpression and/or amplification in human cancers. Herein we report our structure-based optimization strategy of a dibenzodiazepine, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1. Co-crystallization of dibenzodiazepines with PAK1 confirmed binding to an allosteric site and revealed novel key interactions.
4:40 CASE STUDY: Type II Kinase Inhibitors of IRE1 Allosterically Attenuate RNAse Activity to Reduce Apoptosis under Endoplasmic Reticulum Stress
Feroz Papa, M.D., Ph.D., Professor, Department of Medicine, Division of Endocrinology, University of California, San Francisco
Under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1α Kinase-Inhibiting RNase Attenuators-KIRAs-that allosterically inhibit IRE1α’s RNase by breaking breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1α in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration.
5:10 Close of Conference