2017 Archived Content
The human kinome is a large and highly druggable class of targets spanning numerous disease indications, and accounts for a significant portion of drug discovery efforts. Kinase inhibitor discovery remains a very active area as developers are exploring more deeply into the human kinome, 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.
Cambridge Healthtech Institute’s 10th Annual Kinase Inhibitor Discovery conference will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase drug discovery.
Final Agenda
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Wednesday, September 27
11:50 am Conference Registration Open
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Welcome Remarks
Kip Harry, Senior Conference Director, Cambridge Healthtech Institute
2:50 Chairperson’s Opening Remarks
Doriano Fabbro, Ph.D., CSO, Piqur Therapeutics
2:55 Opportunities and Pitfalls in Characterizing Covalent Kinase Inhibitors during Lead Optimization
Christopher Harris, Ph.D., Associate Director, AbbVie
This presentation will discuss a category of experiments that qualitatively confirm the mechanism of action, but are not otherwise enlightening. However, measuring apparent binding (Ki) and reactivity (kinact) components, or their ratio (kinact/Ki), can inform optimization of these components. We will discuss how to measure such at scale. Lastly, this talk will address selectivity: comparing covalent vs. non-covalent selectivity, and how failing to account for time dependence misrepresents off-target liabilities.
3:25 Discovery of the Covalent FGFR1-4 Inhibitor PRN1371 for the Treatment of Solid Tumors
Michael Bradshaw, Ph.D., Associate Director, Principia Biopharma
We have developed a selective, irreversible covalent inhibitor of FGFR1-4, PRN1371, by targeting a cysteine residue within the kinase domain. PRN1371 demonstrates highly selective and long lasting inhibition of FGFR which extends beyond drug clearance from circulation. Strong inhibition was also sustained toward clinically relevant FGFR mutations and translocations. In addition, durable tumor regression was obtained in multiple rodent xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays.
3:55 3DM Protein-Family Analysis Platform Applied to the Kinase Protein-Family
Henk-Jan Joosten, Ph.D., CEO, Bio-Prodict
Vast amounts of data are available for protein-families (e.g., sequences, literature, structural-, alignment-, SNP-, mutation-, patent-, binding data). 3DM, a protein-superfamily analysis platform, automatically collects and integrates all data and contains many state-of-the-art analysis tools. 3DM is used by many companies, including large pharma, to guide structure-based drug design.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Design and Development of a Novel, Selective PI3K-p110β/δ Inhibitor, KA2237, for the Treatment of Cancer
Stephen Shuttleworth, Ph.D., COO and CSO, Karus Therapeutics Ltd.
5:30 Discovery of a PI3Kβ/δ Inhibitor for the Treatment of PTEN-Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template
Stephane Perreault, Ph.D., Research Scientist II, Medicinal Chemistry, Gilead Sciences, Inc.
The design, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template will be presented. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model. Phosphoinositide 3-kinase β (PI3Kβ) signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated.
6:00 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin
Doriano Fabbro, Ph.D., CSO, Piqur Therapeutics
The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.
6:30 Close of Day
6:30 Dinner Short Course Registration
Click here for details on short courses offered.
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Thursday, September 28
7:30 am Registration Open
8:00 Interactive Breakout Discussion Groups with Continental Breakfast
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. Details on the topics and moderators are below. Please click here for full details on all breakouts.
New Kinase Targets in Cancer Immunotherapy
Moderator: Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)
- Biological insights into the immune pathways
- Target validation approaches for novel kinase immunotherapy targets
- Predicting rational combinations
Strategies for Achieving Kinase Inhibitor Activity and Selectivity
Moderator: Istvan Enyedy, Ph.D., Senior Scientist, Drug Discovery, Biogen
- Ligand- and structure-based methods
- Limitations of current methods
- Emerging tools and strategies
9:00 Chairperson’s Remarks
Gerhard Mueller, Ph.D., CSO, Gotham Therapeutics
9:05 Target Residence Time-Guided Optimization of TTK Kinase Inhibitors
Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)
We studied NTRC 0066-0, a selective inhibitor of TTK, together with eleven TTK inhibitors from different chemical classes developed by others. Parallel testing showed that the cellular activity of the TTK inhibitors correlates with their binding affinity and, more strongly, with target residence time. X-ray structures revealed that the most potent inhibitors induce a unique structural conformation. Based on this insight, new TTK inhibitors were developed with longer target residence times and very potent anti-proliferative activity.
9:35 Structure-Based Design of Long Residence Time into Novel Kinase Inhibitors
Gerhard Mueller, Ph.D., CSO, Gotham Therapeutics
The presentation focuses on the engineering of binding kinetic signatures into “deep-pocket-directed” scaffolds for achieving high-efficacy kinase inhibitors. We will demonstrate that a thorough understanding of the precise pharmacophoric requirements on the target’s binding site is essential to pre-engineer the desired slow off-rates into new, thus literature-unprecedented scaffolds that qualify as privileged structures for the target family of kinases. The details of the so-called “retro-design” approach for type II kinase inhibitors will be exemplified by hit-to-lead and lead optimization campaigns that yielded novel and highly efficacious inhibitors for a variety of kinases. Special emphasis will be laid on optimizing selectivity of inhibitors against CDK8, a novel and interesting anti-cancer target.
10:05 KEYNOTE PRESENTATION: Selective Targeting of Kinase Catalytic and Non-Catalytic Function
Stefan Knapp, Ph.D., Professor, Department of Pharmaceutical Chemistry, Goethe Institut, Frankfurt
Advances in kinase structural biology led to an excellent structural coverage of the human kinase family and provided insight into the remarkable domain plasticity of the catalytic domain. Our laboratory contributed 75 of the currently ~200 known crystal structures, enabling a family-wide structural analysis for rational design of inhibitors. In this talk I will summarize strategies that led to the development of highly selective inhibitors. I will discuss the discovery of novel inhibitor binding sites including allosteric sites and the exploitation of unusual structural features for the design of highly selective kinase inhibitors including irreversible inhibitors. Structural aspects optimizing inhibitor residence times and mechanisms leading to slow off-rate binding kinetics will also be discussed.
10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
11:20 Discovery of MLi-2, a Potent, Selective and Brain Penetrant LRRK2 Inhibitor
Jack D. Scott, Ph.D., Principal Scientist, Merck
Starting from a high-throughput screen (HTS), a series of indazole kinase inhibitors was identified. Optimization of these inhibitors based on ligand efficiency (LE), hepatocyte stability and kinome selectivity led to the identification of MLi-2, a very potent and selective LRRK2 inhibitor that showed robust CNS activity in rodent pharmacodynamic studies. Subsequently MLi-2 has been used to identify previously unknown substrates of LRRK2.
11:50 SPEAKER CANCELLATION: Leucettines, a Class of DYRK1A Inhibitors, as Drug Candidates for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease and Down Syndrome
Laurent Meijer, Ph.D., CEO & CSO, ManRos Therapeutics
There is growing evidence implicating the DYRK1A kinase in the onset and development of neurodegenerative pathologies such as Alzheimer’s disease (AD) and Down syndrome (DS). Leucettines, derived from the marine sponge natural product Leucettamine B, represent an archetype of DYRK1A inhibitors. Medicinal chemistry optimization and detailed characterization of Leucettines at the molecular, biochemical, cellular and animal models levels have been carried out extensively. Leucettines are able to cross the blood-brain barrier, to normalize DYRK1A activity, to modify specific phosphorylation patterns and to restore normal cognitive functions in three DS and three AD animal models. These encouraging results advocate for further development of a Leucettine drug candidate as a potential therapeutic agent to treat neurodegenerative diseases and possibly other diseases.
12:20 Enjoy Lunch on Your Own
1:50 Refreshment Break in the Exhibit Hall with Poster Viewing
2:35 Chairperson’s Remarks
Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)
2:40 Data-Driven Design of Kinase Inhibitors with Controlled Polypharmacology
Dmitri Kireev, Ph.D., Professor, Chemical Biology & Medicinal Chemistry; Director, Computational Biophysics & Molecular Design, Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
The presented multidisciplinary study is centered around a novel computational approach based on FRAgments in Structural Environments (FRASE). The approach was applied to develop inhibitors of closely related immunotherapeutic cancer targets MER, AXL and Tyro3. The efficacy and specificity of our new leads have been investigated and confirmed in multiple biochemical, cellular and animal models, including kinome-wide polypharmacology profiling, acute lymphoblastic leukemia (ALL), melanoma and NSCLC cell lines, as well as a pharmacodynamic study in mice.
3:10 Ligand- and Structure-Based Methods in Predicting Kinase Activity and Selectivity
Istvan Enyedy, Ph.D., Senior Scientist, Drug Discovery, Biogen
Ligand-based methods are fast and may be useful for large-scale modeling like filtering large databases or predicting kinase selectivity. For example, Kriging is useful for predicting the activity of compounds of interest when enough experimental data is available. The fake ligands derived from ATLAS solvent mapping are negative images of the binding site and show promise in identifying active compounds when used as queries in ROCS. These methods can successfully complement hybrid and structure-based methods like POSIT, HYBRID, and FRED.
3:40 Session Break
3:55 Using a Vector-Free Microfluidic CellSqueeze Platform
Jonathan Gilbert, Ph.D., Director, Strategic Partnerships, SQZ Biotechnologies
Pfizer collaborated with SQZ to employ a newly discovered vector-free microfluidic platform, which enables us to deliver membrane impermeable small molecules into cells and subsequently assess their cellular activity by various functional assays. As a proof-of-concept, we demonstrated that, upon “squeezing”, a cell impermeable JAK inhibitor probe effectively inhibits the phosphorylation of STAT5 in PBMCs. Finally we show that a series of cell-impermeable JAK inhibitors becomes more potent after squeezing.
4:25 Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Anti-Tumor Agent
Osamu Kurasawa, Ph.D., Principal Scientist, Medicinal Chemistry, Takeda Pharamaceutical Co. Ltd.
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized a thieno[3.2-d]pyrimidinone analogue showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound which exhibited potent cellular activity, excellent kinase selectivity, and anti-tumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed pharmacological study, which was deemed an obstacle to further development. A structure-based approach to circumvent formaldehyde adduct formation culminated in the discovery of TAK-931, possessing a quinuclidine moiety, as a preclinical candidate. In this presentation, the design, synthesis, and biological evaluation of this series of compounds will be presented.
4:55 Close of Conference
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