Kinase Inhibitor Discovery Conference

Cambridge Healthtech Institute 第10回

第15回Discovery on Targetの一翼を担うイベント


Final Agenda


· September 25 Symposium: Immunomodulatory Small Molecules

· September 25 Short Course: Covalent Fragments: Applications in Target-Based and Phenotypic Screens

· September 26-27 Conference: Targeting the Ubiquitin Proteasome System

· September 27-28 Conference: Kinase Inhibitor Discovery

· September 27 Short Course: Introduction to Targeted Covalent Inhibitors

· September 28-29 Symposium: CNS and Neurodegenerative Targets

Wednesday, September 27

11:50 am Conference Registration Open

12:20 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.

4:10 Sponsored Presentation (Opportunity Available)

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.

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 available on the conference website.

Optimizing Next-Generation Kinase Inhibitors

9:00 Chairperson's Remarks

Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV

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 Diversity of Kinase Inhibition Modalities and Their Implications to the Hydrophobic Spine Topology

Gerhard Mueller, Ph.D., Senior Vice President, Medicinal Chemistry, MercaChem BV

A brief overview of the heterogeneity of inhibition modes will be given, followed by introducing the concept of the hydrophobic spine as a regulatory element in kinase activation. Distortion of the hydrophobic spine topology offers new opportunities to engineer selectivity, and to optimize binding kinetic attributes. The prospective engineering of binding kinetic signatures into inhibitors by applying "deep-pocket-directed" scaffolds is exemplified by a lead finding campaign that yielded novel, selective, and highly efficacious CDK-8 inhibitors.

10:05 KEYNOTE PRESENTATION: Targeting Protein Kinases

Stefan Knapp, Ph.D., Professor, Department of Pharmaceutical Chemistry, Goethe Institut, Frankfurt

As part of the Structural Genomics Consortium (SGC) our laboratory has solved a comprehensive set of crystal structure of this large protein family offering new opportunities for the design of selective inhibitors. We are particularly interested developing inhibitors targeting unusual binding modes and novel allosteric binding sites.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Kinase Inhibitors For Cns And Neurodegenerative Disorders

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 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 pm Sponsored Presentation (Opportunity Available)

12:50 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or 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

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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