Over the past decade, kinase drug discovery has resulted in the rapid development of a new generation of anti-cancer drugs. 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. 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 Eighth Annual Kinase Inhibitor Chemistry conference will once again bring together academic and industry leaders to network, collaborate and discuss advances in kinase discovery.

Final Agenda

Tuesday, April 25

12:30 pm Registration

TRENDS IN KINASE INHIBITOR DISCOVERY AND DEVELOPMENT

1:30 Chairperson’s Remarks

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

1:40 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.

2:10 Comparison of Methods for Determination of Drug-Target Engagement in Live Cells

Aleksandra Baranczak, Ph.D., Senior Scientist, Discovery Chemistry and Technology, AbbVie

While the list of potential techniques that enable studies of target engagement is continuously expanding, identification of the best method to evaluate interactions between a ligand and its cellular binding partner(s) remains far from straightforward. We will discuss the applicability of various methods for determining target engagement of reversible and irreversible inhibitors of soluble and membrane kinases in live cells. The strengths and limitations of all methods will be analyzed, as well as their adaptability to high-throughput format assay development.

2:40 Determination of a Focused Mini-Kinase Panel for Early Identification of Selective Kinase Inhibitors

Scott Bembenek, Ph.D., Principal Scientist, Computer-Aided Drug Discovery, Janssen Research & Development

Currently, a rational, systematic, and unbiased method for choosing such a mini-kinase panel that reliably determines a compound’s kinase selectivity profile does not exist. Using a novel in-house deconvolution algorithm, we performed a comprehensive analysis on our extensive kinase data set that has yielded findings far beyond those in the current literature. Indeed, one can construct a mini-kinase panel of optimal size that is very predictive when compared to the corresponding full kinase panel. Comparing this mini-kinase panel to random selection, we find an enrichment of 45.1%.

 

3:10 MOEsaic: Application of Matched Molecular Pairs to Interactive SAR Exploration

Alain Ajamian, Ph.D., Director, Business Development, Chemical Computing Group

With larger data sets and parallel development of different structural series, managing and analyzing structure activity/property relationship data in medicinal chemistry projects is becoming ever more challenging. Tools and methods for the efficient visualization, analysis and profiling of structures thus remain of deep interest. In this work, we will describe a new application, MOEsaic, which can be used to quickly interrogate SAR data through the application of interactive MMP analysis and R-group profiling.

 

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Off-Target Effects of 31 FDA-Approved Small Molecule Kinase Inhibitors on AMP-Activated Protein Kinase

Qiang Shi, Ph.D., Principal Investigator, National Center for Toxicological Research (NCTR), FDA

The clinical use of many small molecule kinase inhibitors (KIs) is often limited by severe organ toxicities, particularly hepatotoxicity and cardiotoxicity. Off-target inhibition of AMP-activated protein kinase (AMPK) contributes to the pathogenesis of sunitinib-induced cardiotoxicity, while secondary activation of AMPK protects regorafenib-induced hepatocyte toxicity. We examined the effects of 31 FDA-approved small molecule kinase inhibitors on AMPK.

5:00 CASE STUDY: Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype Distinct Screening Hits

Mark E. Schnute, Ph.D., Medicine Design, Pfizer

Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to a compound with two orders of magnitude improved potency. Through the modification of tail region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated yielding SphK1 selective, potent SphK1/2 dual, or SphK2 preferential inhibitors.

5:30 Breakout Discussions

6:15 Close of Day

6:30 Dinner Short Courses*

*Separate registration required

Wednesday, April 26

7:45am Plenary Breakfast Presentation: NMR in Fragment-Based Lead Discovery (FBLD)

Stefan Jehle, Ph.D., Product Manager, Bruker BioSpin

NMR is ideally suited for detecting low affinity fragments in solution for FBLD and allows quality control of the screening library on the fly. The large dynamic range with respect to the MW of the target and binding affinities enables its application to a broad range of targets. During this presentation, we will show straight forward NMR methods in FBLD for non-experts, basic principles, data acquisition, data analysis, automation options, software solutions and assay development.

8:30 PLENARY KEYNOTE PRESENTATION

Drug Discovery and Pan-Assay Interference Compounds (PAINS)

Jonathan B. Baell, Ph.D., Professor, Medicinal Chemistry, Monash University

I will discuss issues around the PAINS filter that we published in 2010 and since then has generated much discussion in the industry. The PAINS filter helped explain the difficulties with certain compounds that many hit-to-lead medicinal chemists around the world, principally in academia and small biotechs but to some extent in big pharma also, were encountering. However, because some known drugs contain PAINS, there is the fear that such filters may be too stringent.

9:30 Coffee Break in the Exhibit Hall with Poster Viewing

ADVANCES IN COVALENT INHIBITOR DEVELOPMENT

10:40 Chairperson’s Remarks

Stefan Laufer, Ph.D., Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

10:45 Highly Selective JAK3-Inhibitors with a Covalent-Reversible Binding Mode Targeting a Nitrile Induced Arginine Pocket

Stefan Laufer, Ph.D., Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

JAK3 functions are restricted to immune cells suggesting it as a primary target. However, the high degree of structural conservation makes isoform selective targeting a challenging task. Here we present picomolar inhibitors with unprecedented selectivity for JAK3. Selectivity was achieved by concurrent covalent-reversible targeting of a JAK3-specific cysteine residue and a novel induced binding pocket yielding versatile tool compounds for the elucidation of JAK3 specific functions.

11:15 Bruton’s Tyrosine Kinase (BTK) – Considerations for the Design and Profiling of Irreversible Covalent Inhibitors

Michael Friedman, Ph.D., Principal Scientist, AbbVie

Over the past few years, the interest in covalent inhibitors has increased dramatically with a number of entities entering the clinic and demonstrating significant efficacy. We will describe our approach to identification of the targets appropriate for covalent inhibition. We will describe in detail design of BTK inhibitors with the focus on the ones with high in vivo clearance but durable efficacy. We will present in vivo data including efficacy in the preclinical models.

 

11:45 3DM Protein Family Analysis System Applied to the Kinase Protein Family

Henk-Jan Joosten, Ph.D., CEO, Bio-Prodict

Kinases fall in a very large protein-family. Vast amounts of data are available (>100.000 sequences, literature, structural data, alignment data, SNP data, mutation data (>430.000 in literature), binding data, etc). 3DM, a protein-superfamily analysis platform, automatically collects all data and contains many state-off-the-art tools enabling complex analysis of super-family data.

12:00 pm FEATURED PRESENTATION: Discovery of the Covalent FGFR1-4 Inhibitor PRN1371 for the Treatment of Solid Tumors

Michael Bradshaw, Ph.D., Associate Director, Principia Biopharma

Multiple human cancers contain alterations in FGFRs that drive tumor growth, including translocations, mutations, and amplifications. Recently, clinical studies have demonstrated a utility of FGFR inhibitors for the treatment of FGFR-driven cancers. Challenges remain to identify FGFR inhibitors that do not have off-target inhibition of VEGFR2 and that minimize on-target toxicity. 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. PRN1371 is currently in a phase 1 clinical trial for the treatment of solid tumors.

 

12:30Enjoy Lunch on Your Own

 

1:30 Dessert Break in the Exhibit Hall with Poster Awards

DESIGN AND DEVELOPMENT OF NOVEL ALLOSTERIC MODULATORS

2:15 Chairperson’s Remarks

Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer

2:20 Isoform-Selective Activators of AMP-Activated Protein Kinase for Metabolic Diseases

Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer

AMP-activated protein kinase (AMPK) is a heterotrimeric protein kinase that maintains cellular and whole-body energy homeostasis. We have been seeking specific activators of AMPK for the treatment of cardiovascular and metabolic diseases. High-throughput screening using a novel biochemical assay platform resulted in the identification of multiple chemotypes that target distinct AMPK subunits. We have established the molecular mode of action of these isoform-selective activators through structural, biophysical and kinetic studies. I will describe the medicinal chemistry optimization of the two lead series and biophysical studies of their interactions with AMPK.

Identification of Allosteric Modulators that Induced Conformational Changes in Human Tyrosine Kinases

Gabriel Mercado Besserer, Ph.D., Scientist and Field Application Scientist, Biodesy, Inc.

The role of protein dynamics in biological function and for designing drugs with high affinity, selectivity and long on-target residence time is gaining greater appreciation. Therefore, methodologies sensitive to protein dynamics are required for more efficient screening of compound libraries. However current methods primed for structural dynamics studies lack the throughput needed to screen thousands of compounds. Here we present a novel technique that takes advantage of a non-linear optical phenomenon known as Second-harmonic generation and combines structural sensitivity with high throughput. Using both the kinase domain and the full-length human protein kinases Src and Abl we illustrate the technique’s power for measuring high-throughput real-time kinetics of conformational changes, its conformer-specificity, sensitivity to small structural rearrangements, and the ability to discover allosteric inhibitors including subsequent binding of multiple compounds.

3:20 Germinal-Center Kinase-Like Kinase Co-Crystal Structure Reveals a Swapped Activation Loop and C-Terminal Extension

Laura Silvian, Ph.D., Principal Scientist and Head, Physical Biochemistry, Biogen

We describe here the crystal structure of an activation loop mutant of GLK kinase domain bound to an inhibitor. The structure reveals a weakly associated, activation loop swapped dimer with more than 20 amino acids of ordered density at the carboxy-terminus. This C-terminal PEST region binds intermolecularly to the hydrophobic groove of the N-terminal domain of a neighboring molecule. Although the GLK activation loop mutant crystallized demonstrates reduced kinase activity, its structure demonstrates all the hallmarks of an “active” kinase.

3:50 Refreshment Break

IMMUNOMODULATORY KINASE INHIBITORS

4:20 Structure-Based Design, Synthesis, and Dermal Application of Novel Tyrosine Kinase 2 (TYK2) Inhibitors

Takatoshi Yogo, Ph.D., Principal Scientist, Research, Immunology Unit, Takeda Pharmaceutical Company Limited

We present a discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivatives as a novel chemical series of TYK2 inhibitor. This chemical series was discovered through a unique design strategy, including a hypothesis that an initial lead compound bound to TYK2 with flipped binding mode, as well as structure-based design supported by X-ray crystal structures. Our preclinical candidate exhibited selectivity for IL-23 signaling inhibition against GM-CSF in human PBMC assay, demonstrating the unique cytokine selectivity and the potential of fewer JAK2 related adverse effects.

4:50 Designing Selective Kinase Inhibitors with Quantum Molecular Design

Shahar Keinan, Ph.D., CSO, R&D, Cloud Pharmaceuticals

We report here using QM/MM calculation combined with artificial intelligence (AI) searches and cloud computing to design novel and selective JAK3 inhibitors. The measured activity of our designed molecules for JAK1, JAK2, JAK3 and Tyk2 correlates well with the calculations. Using the multi-object optimization tools in Quantum Molecular Design allows further hit-to-lead optimization, either for percutaneous absorption targeting allergic dermatitis or oral formulation targeting Rheumatoid arthritis.

5:20 Leniolisib (CDZ173) - The Discovery of a New Generation of Selective PI3Kδ Inhibitors

Nicolas Soldermann, Ph.D., Senior Investigator and Group Leader, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

The discovery and characterization of leniolisib (CDZ173), a potent and selective inhibitor of Phosphoinositide 3-kinase delta (PI3Kd) will be presented. We report how innovative medicinal chemistry efforts led to the identification of a novel and promising tetrahydro-pyrido-pyrimidine lead series that could be rapidly further optimized into a favorable physicochemical space and resulted in the identification of leniolisib, currently in clinical development as an anti-inflammatory therapeutic agent. First-in-human study indicated an excellent tolerability, favorable pharmacokinetic properties and a direct PK/PD relationship. Leniolisib is currently undergoing a clinical trial in patients suffering from APDS/PASLI, a disease caused by gain-of-function mutation of PI3Kd. Furthermore, structurally, leniolisib differs significantly from the first generation of PI3Kd and/or PI3Kgd-selective clinical compounds and, therefore, could differentiate favorably in its safety profile.

5:50 Close of Conference

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