2016 Archived Content

Kinase Inhibitor Discovery Header

The human kinome is a large and highly druggable class of targets spanning numerous disease indications, and driving a significant portion of drug discovery and development efforts to date. Despite the hundreds of kinase inhibitors currently in discovery, preclinical, and clinical phases, a relatively small subset of the kinome has been thoroughly explored with selective small molecule inhibitors. Stirred by the clinical success of many approved anti-cancer kinase inhibitors, developers are now finding new ways to expand into a broader portion of the human kinome, move beyond cancer and into chronic diseases, develop immune-modulatory agents as single or combination therapies, shift toward allosteric modulation, and harness irreversible compounds.

Cambridge Healthtech Institute's ninth annual Kinase Inhibitor Discovery meeting will once again unite leading kinase inhibitor discovery and development scientists to discuss emerging targets, tools, and development strategies.

Final Agenda

Best Value

• September 19 Short Course: RNA as a Small Molecule Drug Target

• September 20-21 Conference: Targeting Histone Methyltransferases and Demethylases

• September 21-22 Conference: Kinase Inhibitor Discovery

Day 1 | Day 2 | Download Brochure

Wednesday, September 21

11:20 am Conference Registration Open

11:25 Enjoy Lunch on Your Own

2:40 Refreshment Break in the Exhibit Hall with Poster Viewing


3:20 Chairperson’s Opening Remarks

Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin

Doriano_FabbroDoriano 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.

4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity

Stephen_ShuttleworthStephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.

The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.

4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery

Treiber_DanielDaniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation

InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.

TTP Labtech4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays

Wylie_PaulPaul Wylie, Ph.D., Head, Applications, TTP Labtech

Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing


5:40 Speaker has Cancelled Targeting JAK3 with Covalent Inhibitors

 Chris_BurnsChristopher Burns, Ph.D., Laboratory Head, ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research

Selective inhibition of JAK3 has promise as treatment for autoimmune 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 a series of irreversible potent and selective JAK3-targeted agents will be presented.

5:40 Selected Presentation: Comparative Cancer Cell Line Profiling Differentiates the Mechanism of Action of Different Kinase Inhibitors

Guido_ZamanGuido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

Profiling of drug candidates in cell line panels is an important tool to compare the selectivity and targeting of new anti-cancer agents. In addition, comparative profiling may be used to repurpose established therapeutics by identifying new mechanisms of action or cross-selectivities. A collection of more than 120 anti-cancer agents, targeting all important oncogenic signaling pathways, including classic cytotoxic agents as well as many epigenetic modulators and kinase inhibitors, was profiled on a panel of 44 or 66 parallel cell line proliferation assays (OncolinesT). The OncolinesT profiles of the compounds were compared by Pearson correlations of their inhibitor responses. Inhibitor sets were clustered using hierarchical trees. Response profiles were correlated to the genetic background of the cell lines by Analysis of Variance (Anova). Reproducibility of the NTRC OncolinesT cell panel was validated by monitoring cell growth rate and the variation in IC50s of replicate profiles over a period of three years. The Pearson correlation between replicates ranged between 0.60 and 0.99 for 16 different inhibitors, depending on dose-response curve shape. Correlation analyses of the greater than 120 profiled anti-cancer agents revealed separate clusters of, a.o., taxanes, platins, topo-isomerase inhibitors, and EGFR, ABL, MEK and BRAF inhibitors. This demonstrates that the OncolinesT profiles are an unbiased representation of the compound's mechanisms. The profile of the BTK inhibitor ibrutinib correlated with EGFR inhibitors. In biochemical experiments we showed that this due to its cross-reactivity with EGFR. Profiling of EZH2 inhibitors indicates that there are essentially two classes and that these have a cellular profile that is distinct from HDAC, DOT1L or BET inhibitors. The six Aurora kinase inhibitors profiled fall into two separate clusters, which are related to their biochemical selectivity. Thus, Aurora A-selective inhibitors are relatively more active in cell lines with mutations in cell cycle checkpoint-related genes such as TP53 and RB1; whereas pan-Aurora inhibitors are more active in cell lines with mutations in growth factor signaling pathways, such as NRAS. Profiling of eleven PI3 kinase and mTOR inhibitors revealed four distinct clusters. PI3Kalpha and PI3Kdelta isoform selective inhibitors each target genetically distinct subgroups of cell lines. Rapamycin-analogs, such as everolimus, specifically target PTEN-mutant cell lines. In conclusion, comparative cancer cell line profiling is a powerful tool to rapidly explore the pharmacogenomics of drug action in cancer cells and to identify new or previously un-noted activities of compounds.

6:10 Inhibition of Autoimmune Pathways with Dual Inhibition of JAK1 and TYK2

Suvit Thaisrivongs, Ph.D., Head of Immunoscience Chemistry, Pfizer Worldwide R&D

This work describes the discovery of selective JAK1 / TYK2 inhibitors for a range of inflammatory disorders such as inflammatory bowel disease, systemic lupus erythematosus and psoriasis. Balancing the in-family kinase selectivity is important to optimize the inhibition of pathogenic cytokines while limiting immune suppression, as well as to limit effects driven by JAK2 signaling through EPO. The lead is a well-behaved molecule with excellent in vitro potency and a superior off-target profile.

6:40 End of Day

Day 1 | Day 2 | Download Brochure

Thursday, September 22

7:30 am Registration Open and Morning Coffee


8:30 Chairperson’s Remarks

Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics


Jack_TauntonJack Taunton, Ph.D., Professor, Cellular and Molecular Pharmacology, UCSF School of Medicine, University of California, San Francisco

The clinical utility of targeting kinases with covalent drugs has been firmly established, exemplified by the irreversible kinase inhibitors, afatinib, ibrutinib, and rociletinib. More broadly, targeting a noncatalytic cysteine with an electrophile often results in enhanced potency and selectivity. Motivated by a desire to explore the chemistry of thiol-reactive electrophiles under physiological conditions, we initiated a study of Michael acceptors bearing substituents with increasing electron withdrawing capacity. We were surprised to find that 2-cyanoacrylamides react with simple thiols to form kinetically unstable adducts. We hypothesized that the intrinsically labile nature of the cysteine/cyanoacrylamide bond could be exploited to yield cysteine-targeted, reversible covalent inhibitors. These concepts have led to the design of ultra-selective kinase inhibitors with slow dissociation kinetics. 

9:15 Kinetic Selectivity and Target Residence Time Determine Cellular Activity of Kinase Inhibitors

Guido_ZamanGuido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

We have developed surface plasmon resonance binding assays for more than 50 different protein tyrosine, serine/threonine, and lipid kinases. Results will be presented on the selectivity profiling and determination of binding kinetics of different PI-3 Kinase inhibitor subclasses; a comparison of reversible and irreversible EGFR inhibitor drugs; and the study of the relationship of kinase protein structure, as determined by x-ray protein crystallography, and target residence time for TTK/Mps1. Kinetic parameters and binding characteristics obtained with surface plasmon resonance measurements are compared with potency data from enzyme activity assays and cell-based assays. It is shown that optimization on increased target residence time can result in improved cellular activity of irreversible kinase inhibitors. 

9:45 FEATURED PRESENTATION: Crafting Selective Kinase Inhibitors: The Power of a Fully Annotated Kinase Inhibitor Library

Brian_HodousBrian Hodous, Ph.D., Director, Medicinal Chemistry, Blueprint Medicines

Blueprint Medicines has developed a proprietary kinase inhibitor library. This collection has been designed, synthesized and fully annotated against a panel of over 400 human wild-type kinases and over 50 clinically relevant mutants, in an iterative manner. This annotated library has resulted in the identification of exquisitely potent and selective tool compounds, advanced medicinal chemistry starting points, and unique insights into structural features that are drivers of potency and selectivity. Here we present an overview of how this library has been built and analyzed, and applied to accelerate drug discovery efforts.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:10 Hit-to-Lead Optimization Guided by Information from Focused Mapping

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

Solvent mapping was developed to predict in silico where organic solvent molecules would bind to a protein. Later it was found to be useful for identifying “hot spots” corresponding to “druggable” sites by small molecules. Focused mapping is a method to do a refined exploration of the binding site to highlight key interactions. We evaluated the use of this method for guiding hit-to-lead optimization.

11:40 CASE STUDY: Targeting PLK1 through a Novel Covalent Mechanism

Campbell_McInnesCampbell McInnes, Ph.D., Associate Professor, Drug Discovery & Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina

We will describe novel inhibitors of PLK1 kinase activity that inhibit through a unique covalent strategy. The discovery and optimization of these inhibitors is described in addition to confirmation of their on-target anti-tumor mode of action through selective PLK1 inhibition.

12:10 pm Selected Presentation

12:40 Session Break

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:30 Refreshment Break in the Exhibit Hall with Poster Viewing


2:15 Chairperson’s Remarks

Florence Fevrier-Wagner, Ph.D., Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, Broad Institute

2:20 Covalent Inhibitors that Allosterically Modulate IRE1 Function

David_ThomasDavid Thomas, Ph.D., Chair and Professor, Biochemistry, McGill University

This presentation will describe our work on modulators of IRE1 and their biological effects on ER stress and protein trafficking diseases such as cystic fibrosis. Our data on the mechanism of a covalent inhibitor of IRE1 will be described, as will the results with new IRE1 modulators with a different mechanism of action. The link between IRE1 modulators and the correction of trafficking of ER retained mutant proteins will also be described.

2:50 Selected Presentation 

3:20 Session Break


3:30 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.

4:00 Leveraging Pre-Competitive Risk Sharing to Accelerate the Understanding of LRRK2 Kinase Inhibition as a Potential Disease Modifying Treatment for Parkinson’s Disease

Matthew_FellMatthew Fell, Ph.D., Associate Principal Scientist, Early Neuroscience Discovery, Merck Research Laboratories 

Leucine-rich repeat kinase 2 (LRRK2) gain of function mutations are associated with late-onset autosomal dominant Parkinson's disease (PD) and represent the most common known cause of familial PD. In spite of strong genetic evidence for potential disease modification in PD patients, advancement of LRRK2 inhibitors towards the clinic has been hampered by many factors, including perceived on-target toxicology in preclinical species. To further investigate these findings, medicinal chemistry efforts provided a potent, selective, brain-penetrant molecule enabling further investigation of LRRK2 biology both internally and with collaborators via the Michael J. Fox Foundation (MJFF). This molecule has not only been utilized to explore the biological effects of LRRK2 kinase inhibition (including the discovery of bona fide LRRK2 substrates) but also to probe the tolerability of LRRK2 kinase inhibitors. This compilation of preclinical data and will be discussed.

4:30 Use of Exquisitely Selective Inhibitors of the GSK3 Kinase Isoforms for the Treatment of Fragile X Syndrome and Other Psychiatric and Central Nervous System Disorders

Florence_Fevrier-WagnerFlorence Fevrier-Wagner, Ph.D., Senior Group Leader, Medicinal Chemistry, Stanley Center for Psychiatric Research, Broad Institute

We report the discovery of the first isoform selective inhibitors of GSK3α 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 (>100x selectivity vs. 311 kinases). Our data demonstrate for the first time that the selective inhibition of a single GSK3 isoform is sufficient to rescue three different biochemical or electrophysiological phenotypes in a mouse model of Fragile X.

5:00 Close of Conference

Day 1 | Day 2 | Download Brochure