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Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics

Available via


Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics

Tuesday, May 22, 2018

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Presented By

Biochemical Pharmacology Discussion Group

The New York Academy of Sciences


Over the past few years we have witnessed considerable progress in the field of kinase inhibitors, however there is still no consensus as to which screening methods are best suited to their identification. This symposium will bring together experts in the field of kinase drug discovery to review the landscape, exploring new approaches and technologies driving the advancement of non-classical kinase inhibitor pipeline, and drawing on past lessons to provide insight into the future direction of the field.


Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow
Nonmember Academia, Faculty, etc.
Nonmember Corporate, Other
Nonmember Not for Profit
Nonmember Student, Undergrad, Grad, Fellow
Member Student, Post-Doc, Fellow

Scientific Organizing Committee

Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Lynn Abell, PhD, Agios Pharmaceuticals
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Charu Chaudhry, PhD, Bristol-Myers Squibb
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Amy Hart, PhD, Bristol-Myers Squibb
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Ravi Kurumbail, PhD, Pfizer
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Stephen Noell, MS, Pfizer
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Claire Steppan, PhD, Pfizer
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Sonya Dougal, PhD, The New York Academy of Sciences
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Sara Donnelly, PhD, The New York Academy of Sciences

Keynote Speaker

Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Nathanael S. Gray, PhD, Harvard Medical School


Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Dustin James Maly , PhD, University of Washington
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Kimberly Cameron, PhD, Pfizer
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Elizabeth Goldsmith, PhD, University of Texas Southwestern Medical Center
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Markus Seeliger, PhD, Stony Brook University School of Medicine
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Stephen Wrobleski, PhD, Bristol-Myers Squibb **
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
John Sanders, PhD, Merck
Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics
Adelajda Zorba, PhD, Biogen

**not participating in webinar


May 22, 2018

8:30 AM

Breakfast and Registration

9:00 AM

Introduction and Welcome Remarks


Sonya Dougal, PhD
The New York Academy of Sciences
Ravi Kurumbail, PhD

Keynote Address

9:15 AM

New Approaches to Targeting Oncogenic Kinases


Nathanael S. Gray, PhD
Harvard Medical School

Protein kinases are proven drug targets but in cancer resistance to kinase inhibitor invariable develops.  This lecture will focus on new approaches to target kinases with covalent, allosteric and degradation inducing drugs focusing on CDKs, FLT3, BTK and EGFR.  A new system for validating the effects of small molecule induced protein degradation – the D-TAG approach will also be discussed.

Session 1: Kinase Signaling, Structure, and Allostery

Session Chairperson
Amy Hart, PhD, Bristol Myers Squibb
10:00 AM

Inhibitors of the Hypertension Drug Targets WNK1 and WNK3


Elizabeth Goldsmith, PhD
University of Texas, Southwestern Medical Center

With no lysine (WNK) kinases are associated with familial forms of hypertension and hypotension.  They control the activity of cation-chloride  contransporters both through hormonal activation and direct activation of autophosphorylation by osmotic pressure, and thus are both sensors and effectors of blood pressure.  WNKs have well-characterized functions in the kidney, and in addition have essential functions in brain, the heart and vasculature, as well as secreting epithelia, and are considered drug targets for hypertension, stroke, and secretory diseases such as cystic fibrosis.

Novartis has recently published on pan-WNK inhibitors (Yamada, K. et al. (2016) Nat. Chem. Biol. 12, 896-898). We conducted a screen of  a 200,000 compound library at the UT Southwestern  High Throughput Screening Core and have identified selective inhibitors of both WNK1 and WNK3. The scaffolds of the discovered compounds are distinct for the Novartis compounds, but crystallographic analysis reveals similarities to the binding mode reported previously.

10:30 AM

Networking Coffee Break

11:00 AM

What Makes a Kinase Promiscuous for Inhibitors?


Markus Seeliger, PhD
Stony Brook University School of Medicine

ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a previously published, large kinome profiling dataset we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the remaining 398 kinases. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680. Surprisingly, we find that DDR1 binds these type I inhibitors in an inactive conformation reserved for type II inhibitors. Our computational and biochemical studies show that DDR1 is unusually stable in this inactive conformation. Here, we show for the first time the structural and mechanistic basis for the promiscuity of kinases towards their inhibitors and provide a novel approach to derive structural preferences of kinases through large scale binding assays.

11:30 AM

Delineating the Role of Cooperativity in the Design of Potent PROTACs for BTK


Adelajda Zorba, PhD

PROTAC-based protein degradation is an emerging field that holds significant promise for targeting the “undruggable” proteome: the vast majority of the proteins that do not exhibit enzymatic activity and are thereby not amenable to classical inhibition. Despite significant progress, a thorough mechanistic characterization of biochemical determinants that underpin efficient PROTAC activity is lacking. Here, we address one such question: Is positive cooperativity necessary for potent protein degradation? Through a collection of independent techniques, we show that alleviation of steric clashes within the BTK PROTAC system is both necessary and sufficient for effective in vitro and in vivo degradation. This result broadens the scope of PROTAC applications and impacts fundamental design criteria across the field.

Session 2: Data Blitz Presentations

Session Chairperson
Amy Hart, PhD, Bristol Myers Squibb
12:00 PM

Photoswitchable, Covalent Inhibitors of c-Jun N-terminal Kinase 3


Martin Reynders, MSc
New York University

The c-Jun N-terminal kinase 3 (JNK3), a mitogen-activated kinase, is a key signalling enzyme in cellular stress response. JNK3 is primarily expressed in the nervous system and has previously been targeted by covalent inhibitors for the treatment of neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's disease. Here we introduce the combination of covalent inhibition and photopharmacology. Optical control of JNK3 is achieved using synthetic inhibitors, based on cyclic azobenzene photoswitches, enabling light-control over the degree of covalent modification and thus controlling kinase inhibition. This strategy allows spatiotemporal targeting of JNK3 in research and therapy, providing a general approach of optical control which is applicable to other covalent inhibitors and kinases.

12:05 PM

Redefining the Protein Kinase Conformational Space with Machine Learning


Peter M.U. Ung, PhD
Icahn School of Medicine at Mount Sinai

Protein kinases are dynamic, adopting different conformational states that are critical for their catalytic activity. We assess a range of structural features derived from the conserved aC-helix and DFG-motif to define the conformational space of the catalytic domain of protein kinases. We then construct Kinformation, a random forest classifier, to annotate the conformation of 3,708 kinase structures in the PDB. Our classification scheme captures known active and inactive kinase conformations and defines an additional conformational state, thereby refining the current understanding of the kinase conformational space. Furthermore, network analysis of the small molecules recognized by each conformation captures chemical substructures that are associated with each conformation type. Our description of the kinase conformational space is expected to improve modeling of protein kinase structures, as well as guide the development of conformation-specific kinase inhibitors with optimal pharmacological profiles.

12:10 PM

Discovery of Inactive Conformation-Selective Kinase Inhibitors by Utilizing Cascade Assays


Weixue Wang, PhD
Janssen Research and Development

Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Targeting inactive (versus active) kinase conformations offers advantages in achieving selectivity due to their more diversified structures. Discovery of inactive conformation-selective inhibitors, however, has been hampered partly by the lack of general assay methods. Herein, we present that such inhibitors can be discovered by utilizing kinase cascade assays. This type of assays is initiated with the target kinase in its unphosphorylated, inactive conformation, which is activated during the assay. Inactive conformation-selective inhibitors stabilize the inactive kinase, block activation and yield reduced kinase activity. We investigate properties of the assay by mathematical modeling, as well as by proof-of-concept experiments using the BRAF-MEK1 cascade. The present study demonstrates effective identification of inactive conformation-selective inhibitors by cascade assays, reveals key factors that impact results, and provides guidelines for successful cascade assay development.

12:15 PM

Networking Lunch and Poster Session

Session 3: Structure and Dynamics underlying Kinase Allostery

Session Chairperson
Stephen Noell, MS, Pfizer
1:30 PM

Identification and Structural Characterization of Allosteric, TrkA-Selective Inhibitors


John Sanders, PhD

Substantial unmet medical need exists in the treatment and management of pain, as currently available therapeutic options can result in incomplete pain relief as well as significant side effects. With the identification of Tropomyosin-related kinase A (TrkA) and its association with NGF (the ligand for TrkA) and chronic pain, a novel biological mechanism and candidate for pain management emerged and presented a promising opportunity for therapeutic intervention. Here, we describe a screening approach that resulted in the identification of TrkA-specific inhibitors as well as the structural studies that revealed how the TrkA juxtamembrane domain can contribute to their binding sites, providing their specificity. A high degree of flexibility in the TrkA juxtamembrane domain allows for several distinct binding modes, each of which will be discussed. This knowledge can assist the development of selective TrkA inhibitors and has general implications for screening strategies in drug discovery.

2:00 PM

Allosteric Modulation of Protein Kinases Through Their ATP-Binding Sites


Dustin James Maly, PhD
University of Washington

Protein kinases are one of the most highly pursued targets for the development of new therapeutics by the pharmaceutical industry. A vast majority of potent protein kinase inhibitors act by competing with ATP to block the phosphotransferase activity of their targets. However, there is emerging evidence that ATP-competitive inhibitors can affect kinase interactions and functions in ways beyond phosphotransferase catalytic activity. While most inhibitors are able to interact with the ATP-binding clefts of kinases in an active conformation, a subset are conformation-selective, in that they only bind to their targets if conserved catalytic residues have been displaced from a catalytically competent conformation. The bi-directional allosteric relationship between the ATP-binding clefts and regulatory/scaffolding sites of protein kinases raises the intriguing possibility that these conformation-selective inhibitors may differentially influence phosphotransferase-independent functions of kinases. We have shown that conformation-selective, ATP-competitive ligands are able to differentially modulate regulatory interactions, scaffolding events, and catalytic activities that are distal to their binding sites in diverse protein kinases. Furthermore, we have found that conformation-selective inhibition can lead to divergent phenotypic effects in the cell. An overview of how the phosphotransferase-independent functions of Src-family kinases can be allosterically modulated with ATP-competitive inhibitors will be presented. Furthermore, the molecular logic governing these allosteric effects will be described.

2:30 PM

Networking Coffee Break

Session 4: Kinase Allosteric Modulators: from Bench to Clinic

Session Chairperson
Charu Chaudhry, PhD, Bristol-Myers Squibb
3:00 PM

The Discovery and Characterization of Allosteric AMPK (5' Adenosine Monophosphate-Activated Protein Kinase) Activators


Kim Cameron, PhD

5' Adenosine monophosphate-activated protein kinase (AMPK) is a critical metabolic enzyme involved in maintaining whole body and cellular energy homeostasis.  It functions as a sensor of cellular ATP levels and regulates it by phosphorylating a multitude of substrates.   A heterotrimeric serine/threonine protein kinase, AMPK is comprised of a catalytic α-subunit in complex with regulatory β and γ-subunits.  The presence of multiple gene products for each subunit allows for the assembly of twelve theoretical isoform combinations which differ in expression pattern across tissues and species.  The pharmaceutical industry has been seeking activators of AMPK for the treatment of cardiovascular and metabolic diseases. While developing enzyme inhibitors has been a highly successful endeavor, we are still in the early days of deciphering the rules of the game for the design of enzyme activators. Through high-throughput screening using a novel biochemical assay, we identified isoform-selective AMPK activator leads.  Optimization of one of our isoform selective AMPK activators using classical medicinal chemistry strategies and computational modeling delivered a potent clinical candidate.  We will describe the biochemical, biophysical, and in vivo characterization of our AMPK activators.

3:30 PM

Beyond the Kinase Domain: Discovery of a First-in-Class, Allosteric Inhibitor of TYK2 for the Treatment of Inflammatory Autoimmune Diseases**


Stephen Wrobleski, PhD**
Bristol-Myers Squibb (**not participating in webinar)

Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and is involved in signaling through the receptors for the pro-inflammatory type-1 interferons, IL-12, and IL-23.  As a result, orally-efficacious small molecule TYK2 inhibitors offer promise as an effective treatment for serious inflammatory autoimmune diseases where these cytokines are believed to play a key role. This presentation will describe a chemogenomics approach using a phenotypic screen and kinome-wide profiling data of a compound library to identify novel allosteric inhibitors of TYK2 that act by binding to and stabilizing the TYK2 pseudokinase domain.  Additional screening and medicinal chemistry efforts leading to the discovery of the clinical candidate BMS-986165, a first-in-class highly potent and selective allosteric inhibitor of TYK2, will also be highlighted.

4:00 PM

Panel Discussion: Integrating Approaches to Identify Novel Kinase Inhibitors


Moderator: Charu Chaudhry, PhD
Bristol-Myers Squibb
4:45 PM

Closing Remarks


Charu Chaudhry, PhD
Bristol-Myers Squibb
5:00 PM

Networking Reception

6:00 PM


To view full attendee list, you must first register for the event, then log in to the Academy website. This list is provided for the personal, noncommercial and informational use only of event attendees, in a manner that is consistent with the New York Academy of Sciences’ mission, goals and activities.
  • Agios Pharmaceuticals

  • AssayQuant

  • AssayQuant Technologies, Inc.

  • Biodesy, Inc.

  • Biogen

  • Bristol Myers-Squibb Discovery Chemistry

  • Bristol-Myers Squibb

  • Bristol-Myers Squibb Company

  • Chem & Bio Informatics

  • Cold Spring Harbor Laboratory

  • Cornell University

  • Georgetown University

  • Harvard Medical School

  • HDH Associates International LLC

  • Icahn School of Medicine at Mount Sinai

  • Jaguar Pharma

  • Janssen Research & Development

  • Janssen Research & Development, LLC

  • Johnson & Johnson

  • Korea Advanced Institute of Science and Technology

  • Memorial Sloan-Kettering Cancer Center

  • Merck & Co., Inc.

  • Merck Research Laboratories

  • Mount Sinai Medical Center

  • New York Structural Biology Center

  • New York University

  • New York University NYU

  • NYU Division of Rheumatology

  • Ohio University

  • Pfizer

  • Pfizer Global Research and Development

  • Pfizer Inc.

  • Roche

  • Roche Translational and Clinical Research Center (TCRC)

  • SQI Diagnostics

  • St. Johns University, NY

  • Stony Brook University

  • The Albert Einstein College of Medicine

  • The City College of New York, CUNY* CCNY

  • The Icahn School of Medicine at Mount Sinai

  • The New York Academy of Sciences

  • The Rockefeller University

  • The Telmarc Group

  • Tri-Institutional Therapeutics Discovery Institute

  • University of Washington,Seattle

  • UT Southwestern Medical Center

  • Weill Cornell Medicine