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.
RECOMMENDED PREMIUM PACKAGE:
Choose 2 Short Courses and 2 Conferences/Training Seminars
September 16 Pre-Conference Short Course: SC5: Applications of Artificial Intelligence and Machine Learning in Drug Discovery and Development
September 17-18 Conference: Emerging Ubiquitin and Autophagy Targets
September 18 Dinner Short Course: SC9: Targeted Protein Degradation Using PROTACs, Molecular Glues and More
September 18-19 Conference: Kinase Inhibitor Discovery
Final Agenda
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Wednesday, September 18
11:20 am Conference Registration Open
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
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
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 SPR Binding Studies of Small Molecule Inhibitors of PRMT5
Rebecca Eells, PhD, Associate Director, Biophysical Assays, Reaction Biology Corporation
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
Click here for details on short courses offered.
9:30 Close of Day
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Thursday, September 19
7:00 am Registration Open
7:30 Interactive Breakfast Breakout Discussion Groups
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. Visit the conference website for discussion topics and moderators.
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
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 Orally Active IRAK4 Degraders for Oncology and Autoimmune Diseases
Nello Mainolfi, PhD, Founder and CSO, Kymera Therapeutics, Inc.
Targeted protein degradation combines the power of eliminating a disease-causing protein with the advantages of small molecule circulation in the body. Kymera is pioneering and advancing this technology by designing novel heterobifunctional molecules
that engage the target protein and the E3 ligases to direct the target protein to be selectively degraded by the ubiquitin proteasome system. We have utilized this technology to successfully degrade IRAK4, a key node in innate immunity and cancer.
This talk will describe the investigation of the pharmacology of IRAK4 degraders, in cellular systems and in vivo.
11:55 Sponsored Presentation (Opportunity Available)
12:25 pm Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
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: New Approaches to Challenging Targets in Cancer
Nathanael S.
Gray, PhD, Professor of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute
The development of new anti-cancer therapies continues to be massively outpaced by the rapidly expanding knowledge into the biological mechanisms that underpin the development of cancer. One major obstacle is that many potentially interesting targets
are challenging to drug. This lecture will focus on strategies using covalent inhibitors and small molecule degraders which hold the promise of making many previously challenging targets druggable. In particular, we will focus on the use of these
approaches to target kinases and present some key advantages of small molecule degraders including potency, selectivity and abrogation of non-kinase activity-dependent functions. We will also describe efforts to target KRAS – a notorious
and frequent oncogene that has been recalcitrant to small molecule approaches.
3:10 Novel Strategies for Oncoprotein Degradation
Willem den Besten, PhD, Senior Scientific Researcher, Genentech
Targeted protein degradation has the potential to open the door to therapeutic targets previously deemed undruggable. In this talk, I will present the characterization of two ligase ligands and show how target degradation coupled with modulation of
ligase biology leads to increased cellular efficacy. I will also share results on a new method for inducing the degradation of an ubiquitin ligase.
3:40 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.
4:10 Close of Conference
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