Wednesday, June 6
8:25 am Chairperson’s Remarks
8:30 Discovery of Potent, Selective, and Orally Bioavailable SIK2 Kinase Inhibitors for Multiple Disease Indications
Hariprasad Vankayalapati, Ph.D., Scientific Advisor, Arrien Pharmaceuticals
Salt Inducible Kinase 2 (SIK2) is a centrosome kinase required for bipolar mitotic spindle formation and is a Ser/Thr kinase family member.There are four SIK enzymes – SIK1, SIK2 and SIK3 are required for the signaling triggered by a number of factors and excessive signaling through SIK2-driven pathway is believed to play a critical role in the pathogenesis of large B-cell lymphoma, ovarian cancer, stroke, obesity and type-2diabetes.With the application of our proprietary FFDD approach led to the discovery of potent, selective, orally bioavailable first-in-class inhibitors of SIK2. The lead identification, optimization, SAR, PK and efficacy study details of ARN-3015 series of SIK2 inhibitors will be presented.
9:00 Development of a Mono-Selective CDK7 Inhibitor Lead
Jan Eickhoff, Ph.D., Head of Assay Development and Screening, Lead Discovery, Centrum GmBH
We generated picomolar and mono-selective CDK7 inhibitors through rationale design efforts. Inhibitors from our lead series demonstrated in vivo efficacy in a cancer xenograft model without causing toxic or adverse effects, and even more surprisingly, such highly selective CDK7 inhibitors showed a distinct responder profile of sensitive cell lines from a panel of more than 120 different human cancer cell lines. In addition, with the aid of highly selective CDK7 inhibitors, we were able to gain evidence that CDK7 has upside potential as a target in inflammation, as well as infectious diseases.
9:30 Coffee Break
10:00 Inhibitors of the mTOR Signaling Pathway for Oncology
Arie Zask, Ph.D., Senior Research Scientist, Department of Chemistry, Columbia University
The mTOR-signaling pathway is a key regulator of cell growth and survival that is frequently deregulated in cancer. Rapamycin allosterically inhibits only one functional mTOR complex while ATP competitive inhibitors have the advantage of targeting both mTORC1 and mTORC2, leading to improved efficacy. A key aspect of mTOR inhibitor discovery has been selectivity versus the upstream kinase PI3K. Exquisitely selective molecules have been discovered that rely on subtle variations in the ATP binding pockets.
10:30 Novel Examples of Non-ATP Site Inhibitors
Doriano Fabbro, Ph.D., Executive Director, Expertise Kinase Platforrm, CPC, Novartis Pharma AG
11:00 Targeting the Unfolded Protein Response: Discovery and Characterization of Selective First-in-Class PERK Inhibitors
Jeffrey M. Axten, Ph.D., Director, Medicinal Chemistry, Protein Dynamics DPU, Oncology Business Unit, GlaxoSmithKline
The unfolded protein response (UPR) is integral to a cell’s ability to cope with stress under conditions of nutrient starvation and hypoxia. Protein kinase R (PKR)-like ER kinase (PERK) is one of three primary effectors of the UPR associated with cancer cell survival and tumor growth. This presentation will disclose our discovery of potent, selective PERK inhibitors using a crystal structure of the human PERK kinase domain. The effect of a lead PERK inhibitor on the UPR in cells and human tumor xenografts in mice will be discussed.
11:30 Luncheon Presentation (Opportunity Available) or Lunch on Your Own
1:15 pm Chairperson’s Remarks
1:20 Integrate Structural, Biophysical and Computational Methods to Understand Glucokinase Function and Design Novel Allosteric Activators
Xiayang Qiu, Ph.D., Senior Director, Head of Structure Biology & Biophysics, Pfizer, Inc.
Despite the rapid advances in protein crystallography over the last two decades, SBDD successes still rely mostly on the intuitions of our scientists due to the lack of reliable computational tools to predict affinity, kinetics, thermodynamics, solvation and conformational dynamics. Through glucokinase and other examples, I would like to present our progresses in integrating diverse biophysical methods to strengthen the link between structure and function, and advocate for the development of predictive computational algorithms through expanded experimental datasets.
1:50 Structure-Guided Design of Biologically Active and Highly Selective Inhibitors of CK1-ð Protein Kinase
Scot Mente, Ph.D., Senior Research Scientist, Neuroscience Chemistry, Pfizer
Structure-guided design of biologically active and highly selective inhibitors of CK1-ð protein kinase for the treatment of neurological disorders. The CK1 family of protein kinases consists of seven moderately conserved isoforms in humans. This talk will highlight efforts aimed at finding potent and selective ligands for the CK1-d isoform as a circadian rhythm modifying agent.
2:20 Rational Approaches to Improving Selectivity in Drug Design
Woody Sherman, Ph.D., Vice President, Applications Science, Schrodinger Inc.
2:50 Refreshment Break in the Exhibit Hall with Poster viewing
3:30 Identification of DYG-out Inhibitors of LRRK2 Based on Structural Modeling and Enzyme Kinetic Studies
Min Liu, Ph.D., Assistant Director, The Laboratory of Drug Discovery for Neurodegeneration, LDDN, Harvard NeuroDiscovery Center, HNDC, Brigham and Women’s Hospital
Leucine-rich repeat kinase2 (LRRK2), a large and complex protein that possesses two enzymatic properties, kinase and GTPase, is one of the major genetic factors in Parkinson’s disease (PD). Over 40 mutations in LRRK2 have been found in the most common familial forms and some sporadic forms of PD, and have been associated with typical idiopathic, late-onset PD. Here we report the identification of DYG-out inhibitors of LRRK2 based on the combined structural modeling and enzyme kinetic studies.
4:00 Determining the Crystal Structures of Allosteric Kinase Inhibitor Complexes
Barbara Brandhuber, Ph.D., Director, Early Drug Discovery, Biology, Array BioPharma
Upon discovery of a kinase inhibitor that does not appear to bind in the ATP-binding cleft, structural biologists are challenged to determine the crystal structure of the inhibitor-bound kinase to enable structure-based drug design. Frequently, the inhibitor does not crystallize with a canonical kinase construct and therefore a new crystallographic effort is launched. In this presentation, several biochemical, biophysical, and bioinformatic approaches will be discussed which enable and complement crystallographic studies. The use of multi-disciplinary approaches to crystallographically determine the unique binding mode of an allosteric inhibitor interacting with both the regulatory pleckstrin-homology and kinase domains of AKT-1 will be described.
4:30 In silico Lead Finding through Holistic Understanding of Screening Data from Multiple Approaches
Meir Glick, Ph.D., Head, Lead Discovery Informatics, Novartis Institutes for BioMedical Research, Inc.
Understanding of biochemical, biophysical, pathway and functional information is critical for decision making and hypothesis generation in drug discovery. We will discuss the in silico approaches to support this challenge. For example, design of bio-diverse compound libraries and intentional targeting of a specific phenotype. Next, we will describe how the data should be mined and visualized to enable understanding of the molecular mechanism of action and prioritize the right chemical matter for a chemistry program.
5:00 Close of Conference