Cambridge Healthtech Institute’s 9th Annual

Kinase Inhibitor Chemistry

Emerging Approaches for the Discovery and Design of Kinase Inhibitors

April 3-4, 2018 | Hilton Bayfront | San Diego, California

Over the past decade, kinase drug discovery has resulted in the rapid development of a new generation of anti-cancer drugs. As kinase inhibitor discovery remains an active area for a significant portion of all efforts, developers have found new ways to expand into a deeper portion of target space within the human kinome, moved beyond cancer and into chronic disease indications such as CNS disorders, as well as shifted toward allosteric modulation, and harnessing slow-off or irreversible compounds. Cambridge Healthtech Institute’s 9th 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 3

7:00 am Registration and Morning Coffee


8:00 Welcome Remarks from Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Gerhard Mueller, PhD, CSO, Gotham Therapeutics

8:10 FEATURED PRESENTATION: Selective Targeting of Kinase Catalytic and Non-Catalytic Function

Stefan Knapp
Stefan Knapp, PhD, 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.

8:40 Structure-Based Design of Long Residence Time into Novel Kinase Inhibitors

Gerhard_MuellerGerhard Mueller, PhD, 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.

9:10 Selected Poster Presentation: Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors

Mohamed_El-SayedMohamed El-Sayed, Research Assistant, Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy

The present account describes the discovery and development of a new JAK inhibitory chemotype that has produced selective JAK inhibitors, especially vs. JAK1. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to explore the structure-activity relationships of the new substances. Several compounds showed low nanomolar potency against the four members of the JAK family. Compounds 17d and 18 were the most active with single digit nanomolar IC50 values against JAK3 and JAK1. Compound 20a, with an azetidine amide side chain, showed the best selectivity for JAK1 kinase vs. JAK2, JAK3 and TYK2, with low nanomolar potency (3.3 nM). We confirmed efficacious inhibitor activities of many of the compounds on the proliferation and production of inflammatory cytokines by primary T cells.

9:25 Selected Poster Presentation: Discovery of Encorafenib, a Potent, Selective RAF Kinase Inhibitor for Treatment of BRAFV600E-Positive Melanoma

Shenlin_HuangShenlin Huang, Ph.D., Senior Investigator, Medicinal Chemistry, Genomics Institute of the Novartis Research Foundation

Activating mutations of BRAF, especially V600E BRAF, are found in multiple cancers, most notably in melanoma, where approximately 40% of cases are BRAF-V600E positive. Presented is encorafenib (LGX818), a selective small molecule mutant-BRAF kinase inhibitor that suppresses the RAF-MEK-ERK pathway in tumor cells expressing activating BRAF-V600 mutations. In rodent BRAF-V600 tumor xenograft models, LGX818 induces sustained tumor regression at low doses and is well-tolerated. LGX818 has shown an excellent preclinical safety profile. Multiple clinical trials are underway with LGX818 in patients harboring mutant-BRAF solid tumors.

9:40 Coffee Break

10:05 Target Residence Time-Guided Optimization of TTK Kinase Inhibitors

Rogier_BuijsmanRogier C. Buijsman, PhD, Head, Chemistry, 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.

Lonza tagline stacked 10:35 Transforming Kinase Inhibitors into New Lipophilic Salt Forms for Optimized Oral Absorption

Hywel D. Williams, PhD, Principal Scientist, Pharma Sciences, Lonza Pharma & Biotech
Low aqueous solubility continues to feature in kinase inhibitor chemistry, which, to the development scientist, creates the risk of low, variable oral absorption, food-effects and absorption related drug‒drug interactions. In this talk, we will discuss the value of selecting lipophilic salt forms in order to tailor kinase inhibitor properties to a formulation approach that is used to overcome solubility challenges (without altering drug structure). The benefits close working relationships between chemists and formulators in overall drug development is also discussed.

11:05 Determination of a Focused Mini-Kinase Panel for Early Identification of Selective Kinase Inhibitors

Scott_BembenekScott Bembenek, PhD, 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%.

AssayQuant Technologies 11:35 Luncheon Presentation: CSox-Based Sensors for Continuous, Homogeneous and Quantitative Monitoring of Protein Kinase and Phosphatase Activity

Erik SchaeferErik Schaefer, President & CSO, AssayQuant Technologies

AssayQuant® is combining chelation-enhanced fluorescence, via the sulfonamido-oxine (Sox) chromophore, with high-throughput peptide synthesis methods to identify optimized physiologically-based substrates for measuring the activity of protein kinases and phosphatases. The result is a simple yet powerful method that allows continuous, quantitative and homogenous detection of activity using recombinant enzymes or crude cell or tissue lysates. This approach provides a quantum improvement in assay performance and productivity needed to accelerate discovery and drug development efforts.

12:20 pm Session Break


1:15 Chairperson’s Remarks

Stefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

1:20 Presentation I: Design & Development of Highly Selective JAK3 Probes (Janus Kinase 3): Exploring the Arginine-Pocket

Stefan_LauferStefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

Covalent Inhibitors belong to the oldest and most successful drugs. Prominent examples are e.g. Acetylsaliclic Acid, ß-Lactone Antibiotics or Gastric Proton Pump Inhibitors. A major breakthrew in cancer therapy of the last decades was targeted therapy with protein kinase inhibitors. Still unmet needs in this field are target residence time, selectivity and rapid development of target kinase mutations. A very seminal approach to address these issues was described 2013 by Liu et al. “Targeting the Cysteinome“: We applied this strategy to unsolved problems in the field of JAK3, JNKs and mutant EGFR kinases. JAK3 signaling is a key driver in the development of lymphoid cells and modulation of immune response. Due to its isolated expression in lymphocytes a selective JAK3 inhibitions is considered to be a promising strategy for the development of new immunosuppressant drugs. Via a covalent-reversible inhibition approach we were able to develop new highly potent JAK3 inhibitors with high isoform specificity as well as an outstanding kinome wide selectivity. A novel binding mode was observed in the x-ray structure.

1:50 The Meisenheimer Complex as a Novel Paradigm in Drug Discovery: Targeting PLK1 through a Novel Covalent Mechanism

Campbell_MclnnesCampbell McInnes, PhD, Professor, Drug Discovery and Biomedical Sciences, 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.

2:20 A Kinase Platform for the Discovery of Reversible and Covalent Kinase Inhibitors

Igor_MochalkinIgor Mochalkin, PhD, Associate Director, Medicinal Chemistry & Lead Optimization, EMD Serono, Inc.

This kinase platform included a combination of fragment screening, kinase-focused library design and scaffold hopping, tailored for individual kinases, kinase mini-panels and the human kinome. I will highlight our implementation of the kinase technologies that were coupled with medicinal and computational chemistry to identify and develop three clinical kinase-inhibitor candidates from EMD: evobrutinib, M7583 and M2698.

2:50 Presentation II: Triple Mutant EGFR: Report of an Irreversible EGFR Inhibitor with Low Nanomolar Activity Against L858R_T790M_C797S Resistance Mutant

Stefan_LauferStefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

The emergence of mutations within the catalytic domain of EGFR has led to resistances against small molecular drugs. By the application of a scaffold hopping approach, we successfully developed picomolar covalent-irreversible inhibitors against gefitinib resistant EGFR mutants with high cellular activity (14 nM). Moreover we further improved the reversible binding patterns of this chemotype to yield compounds showing high activities in the low nanomalar range against the clinically challenging osimertinib resistant L858R/T790M/C797S triple mutant.

Pelago 3:20 Accelerated Drug Discovery with CETSA®

Michael DabrowskiMichael Dabrowski, CEO, Pelago Bioscience

Using CETSA, researchers can now measure directly how a compound interacts with target proteins in the cell. CETSA can be used against known targets or in an unbiased proteomic approach that makes it ideal for target deconvolution, safety studies and for biomarker discovery.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Sponsored Plenary Keynote Introduction (Opportunity Available)

4:40 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt
Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute
To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic: Increasing Target Residence Time for Kinase Inhibitors

Stefan Laufer, PhD, Chairman, Pharmaceutical & Medicinal Chemistry, Pharmacy & Biochemistry, University of Tuebingen

  • How long is long enough?
  • Type-1, 1.5, 2, covalent reversible, irreversible inhibitors
  • Warheads beside acrylamides
  • On/off rates, methods to determine

Topic: Allosteric Kinases Inhibitors

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

  • Why do we care about allosteric kinase inhibitors?
  • Which screening methods have been most fruitful for identification of allosteric kinase inhibitors?
  • Do allosteric kinase inhibitors possess similar efficacy as ATP-competitive inhibitors?
  • What are some of the most useful panels to assess kinome selectivity of allosteric inhibitors?

Topic: Drugging the Undruggable

Daniele Andreotti, Director, Head, Medicinal Chemistry 3; Drug Design and Discovery, Evotec

  • Current approaches and potential strategies to opening up more targets to drug development
  • What strategies are amenable to hit identification in the absence of structural information?
  • How chemical library design is evolving to meet the specific challenges of post-genomic drug discovery


8:30 Chairperson’s Remarks

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

8:35 Fragment-Based Discovery of Inhibitors of ERK Kinase

Marc O’Reilly, PhD, Senior Director of Molecular Sciences, Astex Pharmaceuticals

This work describes the discovery of highly selective, orally bioavailable, allosteric/bitopic inhibitors of ERK kinase which show robust anti-tumor activity in a range of animal models.

9:05 Isoform-Selective Activators of AMP-Activated Protein Kinase for Metabolic Diseases

Ravi_KurumbailRavi G. Kurumbail, PhD, 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.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing


10:30 Optimization of Brain Penetrant ATM Kinase Inhibitors for the Treatment of Huntington's Disease

Leticia_Toledo-ShermanLeticia Toledo-Sherman, PhD, Director of Computer-Aided Drug Design and Medicinal Chemistry, Chemistry, CHDI Foundation

The presentation will be centered on our efforts to attain potent, selective and brain penetrant ATM kinase inhibitors as proof-of-concept agents for HD. Importantly we demonstrate strong in vitro-in vivo correlations and a robust PK/PD relationship that warrant further studies with these compounds.

11:00 A Journey in the Kinome: Approaches, Strategies and a Bit of Luck

Daniele_AndreottiDaniele Andreotti, Director, Head, Medicinal Chemistry 3; Drug Design and Discovery, Evotec
An overview of the main approaches and therapeutic area where eukaryotic and prokaryotic kinase inhibitors find application will be described. The presentation will be completed by reporting a successful example of Integrated Drug Discovery program. Implementation of a proper approach and strategy have allowed to identify valuable candidates within the agreed timelines and budget.

11:30 Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors - Analysis of Structure-Kinetic Relationships

Masato_YoshikawaMasato Yoshikawa, PhD, Principal Scientist, CNS Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited

We will present a discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel chemical series of brain-penetrating RIP1 kinase inhibitors. The optimization by utilizing SBDD approach led to the discovery of a highly potent, orally active, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Our preclinical candidate significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of the candidate (10 mg/kg, bid) attenuated disease progression in the mouse EAE model of multiple sclerosis.

12:00 pm End of Conference