The human kinome is a very large and druggable class of targets with many disease indications. Thus, the kinome targets account for a significant portion of drug discovery efforts. Kinase inhibitor discovery is a very active area as developers explore
more deeply into designing immune-modulatory agents as single or combination therapies, tackling chronic disease indications such as inflammation and CNS disorders as well as effectively harnessing allosteric modulators and covalently binding compounds.
This year we'll also be discussing PROTACs and the role of artificial intelligence in kinase inhibitor discovery.
Final Agenda
Wednesday, September 18
11:20 am Conference Registration Open (America Foyer)
12:20 pm Event Chairperson’s Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction
Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd
12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University
1:20 PROTACs: Past, Present, and Future
Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing (America Ballroom)
2:45 Organizer's Welcome Remarks
2:50 Chairperson’s Opening Remarks
Mary M. Mader, PhD, Vice President, Chemistry, Relay Therapeutics, Inc.
2:55 Targeting Human Pseudokinases with Kinase Inhibitors
Patrick Eyers, PhD,
Professor, Cell Signaling, Biochemistry, University of Liverpool
Protein pseudokinases are atypical (usually inactive) members of the human kinome. The thriving pseudokinase field is strongly placed to benefit from decades of research undertaken on canonical protein kinases, and the approval of ~50 kinase inhibitors
in oncology and inflammatory indications. In this talk, I will focus on the serendipitous discovery of covalent modulators of Tribbles 2 (TRIB2) pseudokinase, which induces a conformation that drives TRIB2 degradation in human cells.
3:25 Brain Penetrant Kinase Chemotherapeutics: Learnings from CNS Discovery
Mary M. Mader, PhD, Vice President,
Chemistry, Relay Therapeutics, Inc.
Brain penetrance is significantly impacted by the physicochemical properties of the drugs. Compound properties associated with brain penetrance have been analyzed recently for kinase inhibitors in glioblastoma trials, although many of these examples exploit
opportunities identified in clinical development rather than specific compound design strategies. An examination of kinase inhibitors that were optimized specifically for CNS indications could provide insight into preferred property space and lead
to greater success in neuro-oncology efforts.
3:55 KiPIK, a New Inhibitor-Based Approach to Identify Kinases for Specific Phosphorylation Sites
Jonathan Higgins, DPhil, Professor of Eukaryotic Molecular Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University
There are thousands of known cellular phosphorylation sites, but it remains difficult to identify the kinases responsible for particular phosphorylation events. To address this, we describe a general method that exploits libraries of broadly-profiled
protein kinase inhibitors. The inhibition profile for each kinase provides a ‘fingerprint’ that allows unknown kinases acting on target phosphosites in cell extracts to be identified. The method may be useful in both discovery science
and precision medicine.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Discovery and Development of PI4KIIIβ Inhibitors with a Unique Immuno-Suppressive Phenotype Enabling the Prolongation of Allogeneic Organ Engraftment
Helen Horsley, Senior Principal Scientist, Medicinal Chemistry, UCB Pharma
The target of a novel series of immunosuppressive piperazine ureas is the lipid kinase PI4KIIIβ and a link between inhibition of PI4KIIIβ and suppression of immune responses in vitro and in vivo has emerged. Here we detail the identification of UCB9608 and discuss the binding mode and selectivity profile of this novel inhibitor, and the implications this may have on the observed tolerogenic phenotype.
5:30 Targeted Therapy in Patients with PIK3CA-Related Overgrowth Syndrome
Guillaume
Canaud, MD, PhD, Professor of Medicine, Hôpital Necker Enfants Malades, Paris
PIK3CA-related overgrowth syndromes (PROS) are genetic disorders that result from somatic gain-of-function mutations of the PIK3CA gene. PROS has no specific treatment. We created the first mouse model of PROS that recapitulates the human disease and
demonstrated the efficacy of BYL719, PIK3CA inhibitor. On the basis of these results, we used BYL719 to treat 19 patients with PROS. The drug improved the disease symptoms in all patients and was not associated with any substantial side effects.
6:00 Artificial Intelligence in Kinase Inhibitor Discovery
Istvan J. Enyedy,
PhD, Principal Scientist, Biogen
Machine learning in combination with automated inhibitor optimization and statistical analysis may be used to accelerate kinase inhibitor discovery. The performance of a prototype artificial intelligence protocol will be presented.
6:30 Dinner Short Course Registration (America Foyer)
Click here for details on short courses offered.
9:30 Close of Day
Thursday, September 19
7:00 am Registration Open (America Foyer)
Essex Ballroom
7:30 Interactive Breakfast Breakout Discussion Groups - View All Breakouts
Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future
collaborations around a focused topic.
What Are the Next Actionable Precision Oncology Approaches?
Moderator: Vijaya Tirunagaru, PhD, VP, Head of Biology and Non-Clinical Development, Research, Rain Therapeutics
- Technologies to identify novel oncogenic drivers
- Mapping of driver mutations to specific patient populations
- Synthetic lethality approaches
Artificial Intelligence in Kinase Drug Discovery and Development
Moderator: Istvan J. Enyedy, PhD, Principal Scientist, Biogen
- Use of AI in kinase inhibitor drug design and optimization
- Pros and cons of AI in drug discovery
- What is a novel kinase inhibitor and how can we expand the chemical space of kinase inhibitors?
8:30 Transition to Sessions
8:40 Chairperson’s Remarks
Istvan J. Enyedy, PhD, Principal Scientist, Biogen
8:45 Characterization of HER2 Mutations Identified in a Patient with an Initial Response and Acquired Resistance to Neratinib
Ariella B.
Hanker, PhD, Assistant Professor, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center
HER2 is mutated in 2-4% of breast cancers. We identified a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to the HER2 TKI neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive,
gain-of-function mutation. The patient exhibited a sustained partial response on neratinib. Upon progression, acquired HER2T798I was detected. Structural modeling and laboratory studies showed that HER2T798I prevented neratinib binding, which
was overcome by afatinib.
9:15 Discovery of BLU-667 for RET-Driven Cancers
Jason Brubaker, PhD, Director of Chemistry, Blueprint Medicines
BLU-667 is an oral precision therapy designed for highly potent and selective targeting of oncogenic RET alterations and resistance mutants. Our fully annotated kinase inhibitor library was used to identify several RET inhibitor scaffolds. The optimization
of these starting points to lead to the discovery of BLU-667 will be described.
9:45 Targeting PI3K-gamma with IPI-549, a Tumor Macrophage-Reprogramming Small Molecule, in Patients with Advanced Solid Tumors
Jeffery L. Kutok,
MD, PhD, CSO, Infinity Pharmaceuticals, Inc.
IPI-549 is a first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms tumor macrophages from an immune-suppressive (M2) phenotype, to an immune-activating (M1) phenotype and can overcome intrinsic resistance to
checkpoint inhibitors. A Ph 1/1b study IPI-549-01 (NCT02637531) is evaluating the safety, efficacy, tolerability, pharmacokinetics, pharmacodynamics, and immunomodulatory activity of IPI-549 as monotherapy and combined with nivolumab, in over
200 patients with advanced solid tumors.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (America Ballroom)
10:55 Tarloxotinib, a Hypoxia Activated Prodrug for EGFR and HER2 Exon 20 Insertion Mutant NSCLC
Vijaya
Tirunagaru, PhD, VP, Head of Biology and Non-Clinical Development, Research, Rain Therapeutics
EGFR and HER2 exon 20 insertion mutations in non-small cell lung cancers are resistant to current EGFR inhibitors and lack effective therapy. The similarity of exon20 insertions to WT EGFR in the drug binding pocket limits the therapeutic window for
WT EGFR mediated toxicities. Tarloxotininb selectively releases active EGFR inhibitor in the hypoxic tumors and enhances tumor dose intensity while minimizing systemic toxicities.
11:25 NEW: Targeted Degradation of IRAK4 Protein Via Heterobifunctional Small Molecules for Treatment of MYD88 Mutant Lymphoma
Matthew Weiss, PhD, Head, Chemistry, Kymera Therapeutics
KYM-001 is a first-in-class, potent, selective and orally active IRAK4 degrader that causes tumor regression in ABC-DLBCL models. Degradation of IRAK4 removes both the kinase and scaffolding functions of IRAK4 and may be superior to kinase inhibition
alone. These data support IRAK4 degraders as a promising new therapeutic opportunity for MYD88-driven lymphoma, both alone and in combination with other targeted approaches such as BTK inhibition.
11:55 SELECTED POSTER PRESENTATION: Identifying New Drug Targets by Illuminating the Druggable Genome
Karlie R. Sharma, PhD, Program Officer, National Center for Advancing Translational Sciences. National Institutes of Health
Existing clinical drugs only target a few hundred of the ~3,000 genes considered to be druggable, leaving a sizable subset of proteins within three druggable protein families (ion channels, GPCRs and kinases) that still remain largely understudied.
To address this, the National Institutes of Health (NIH) Common Fund has launched the Illuminating the Druggable Genome (IDG) Program, with the overall goal of catalyzing research to improve our understanding of the properties and functions of
proteins that are currently not well studied within commonly drug-targeted protein families.
12:25 pm Session Break
12:35 Luncheon Presentation: Use of InCELL Pulse™
Cellular Thermal Shift Target Engagement Assays in Early Drug Discovery
Paul Shapiro,
PhD, Group Leader, Assay and Product Development, Research and Development Department, Eurofins DiscoverX
A common problem in early target-based drug discovery is the lack of correlation between potencies, or even rank order of potencies, derived from initial biochemical screens and those observed in cellular assays. In phenotypic screening approaches,
often the actual drug target is unknown and needs to be identified and proven. Cellular thermal shift assays for target engagement are of increasing interest because they bridge these gaps, however, existing technologies have been cumbersome and
low-throughput. InCELL Pulse™, using Eurofins DiscoverX Enzyme Fragment Complementation technology, is a rapid, homogeneous, cell-based assay based on ligand-induced changes in protein thermal stability and is used to study drug-target engagement
in live cells. We have successfully applied InCELL Pulse™ to rapidly measure quantitative cellular target engagement potency values for ligands of diverse intracellular protein classes such as kinases, methyltransferases, and hydrolases.
1:25 Refreshment Break in the Exhibit Hall with Poster Viewing
2:05 Chairperson’s Remarks
Nello Mainolfi, PhD, Founder and CSO, Kymera Therapeutics, Inc.
2:10 KEYNOTE PRESENTATION AND DISCUSSION: Targeting Kinases for Degradation- Challenges and Opportunities
Nathanael S.
Gray, PhD, Professor of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein
targets. In this talks I will discuss our efforts to develop chemoproteomic strategies to identify degradable kinases. Methods to characterize small molecule kinase degraders will also be discussed.
3:10 E3 Ubiquitin Ligases for PROTACs Discovery
Matthieu Schapira, PhD, Principal Investigator, Structural Genomics Consortium and Associate Professor, Pharmacology & Toxicology, University of Toronto
To be active, a PROTAC must induce the formation of a productive complex between a target of interest and a structurally and functionally compatible E3 ubiquitin ligase. Considering that less than ten E3 ligases out of over 600 in the human proteome
are exploited by current PROTACs, extending the repertoire of lig-ands to E3 ligases with a variety of structural properties as well as diverse temporal and spatial expression profiles should considerably expand potential applications of PROTACs
for chemical biology, and broaden the horizon for future drug discovery efforts. I will review the classification, ubiquitin-proteasome system association, tissue expression profile and druggability of human E3 ligases.
3:40 Close of Conference