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Wednesday, April 8
7:45 Morning Coffee
8:15 Chairperson’s Remarks
8:20 KEYNOTE PRESENTATION
A Helix Scaffold for the Assembly of Active Protein Kinases
Alexandr Kornev, Ph.D., Chemistry and Biochemistry and Pharmacology, UC San Diego; Howard Hughes Medical Institute
9:00 Breakout Discussion Feedback by Moderators
9:30 Iterative Kinase Medium-Throughput Screening with 2D profile-QSAR and 3D AutoShim Models
Eric Martin, Ph.D., Novartis Institutes for Biomedical Research
Experimental high-throughput screening of a large (1.5 million) compound collection typically takes 6 months and costs $1,000,000. A faster, cheaper, alternative iteratively combines medium-throughput screening with kinase family-based modeling. 2D profile-QSAR models greatly improve kinase prediction accuracy by including data and models from all previously tested kinases. 3D surrogate AutoShim docking models are far more accurate than conventional docking even for novel chemotypes, are as fast as 2D models, and don’t require a target crystal structure. Trained with a modicum of IC¬50¬ data, the majority of active compounds in the archive can be identified with few false positives.
10:00 Networking Coffee Break in the Exhibit Hall
10:45 Fragment-Based Design of Non-ATP Competitive Kinase Inhibitors through REPLACE
Campbell McInnes, Ph.D., Assistant Professor, Pharmaceutical and Biomedical Sciences, University of South Carolina
We describe and exemplify a unique strategy for Fragment based design which involves an interative process for the conversion of peptidic substrate competitive kinase inhibitors to more drug like compounds. We report the application of these methods involving high-throughput docking and synthetic chemistry to produce small molecule peptide hybrid compounds that represent useful lead compounds for further development. These techniques have been valiDated towards CDK2/cyclin A substrate recruitment and more recently have been applied to an additional target that is of interest in Oncology. We discuss progress with the development of non-competitive CDK2/cyclin A kinase inhibitors and application of the REPLACE methods to additional targets.
11:15 Fragment Based Lead Generation for Novel Kinase Inhibitors: Frontloading-Binding-Kinetic Properties
Gerhard Mueller, Ph.D., Chief Scientific Officer & Managing Director, Proteros fragments, GmbH
This presentation highlights a novel kinase inhibitor design approach, notably the “retro-design”. It takes advantage of a fragment-based lead assembly strategy that intentionally avoids the adenine binding region, which is in complete contrast to the majority of the traditionally pursued approaches towards kinase inhibitors. The main advantage of the retro-design strategy is that distinct binding kinetic attributes can be pre-engineered into the resulting lead structures on a fragment basis, thus yielding in kinase inhibitors with slow dissociation rates (koff), i.e. long residence times on the respective target kinases. It has been systematically shown that the desired binding kinetic properties translate into candiDates with high in-vivo efficacy. This presentation will introduce the underlying enzymology the design and application of a tailor-made fragment library, the medicinal chemistry routes for fragment confirmation and fragment evolution, as well as fragment-directed protein crystallography as one of the main enabling technologies for successful drug design.
11:45 Panel Discussion
12:15pm Luncheon in the Exhibit Hall
1:55 Chairperson’s Remarks
Steven Muskal, Ph.D., CEO, Eidogen-Sertanty
2:00 Using Receptor-site Similarity to LigandCross into new Diversity
Steven Muskal, Ph.D., CEO, Eidogen-Sertanty
For several years, researchers have leveraged protein sequence and structural similarity in numerous ways, including but not limited to target hypothesis, target prioritization, ligand design, lead optimization, etc. With the rapidly growing body of currently over 50K publicly available apo- and co-complex structures, automated design of novel matter by ligand hybridization or LigandCross is well positioned in any fragment-based design effort. In particular, numerous Kinase co-complex structures have become available which offer a rich source of information for productive ligand shuffling. Validated examples of LigandCross will be presented
2:30 Discovery and Preclinical Development of Novel Protein Kinase C Inhibitors
Stefan Grant, Ph.D., Senior Director, Biochemical Pharmacology, Pfizer La Jolla Laboratories
PKC signaling is involved in many cellular processes and has been implicated in the pathogenesis of various diseases such as cancer and diabetic microvascular complications. Several clinical trials are ongoing with staurosporin or bisindoylmaleimide-based PKC inhibitors with some promising results. The development of more selective PKC inhibitors may prove to be more efficacious. This talk will provide an overview of a new of potent and selective PKC inhibitors.
3:00 Networking Refreshment Break
3:20 MEK Inhibitor for Oncology and Inflammation – A Developing Story
Jeffrey N. Miner, Ph.D., Senior Director, Inflammation and Oncology, Ardea Biosciences
We have developed several series of MEK inhibitors using structure-based drug design. These compounds bind directly to the allosteric pocket within the MEK enzyme and have potent anti-cancer and anti-inflammatory activity in vivo. An extensive SAR has led to the selection of RDEA119 and RDEA436 for clinical evaluation. These compounds exhibit significant synergy with multiple oncologic agents suggesting a path to enhance existing therapies.
3:50 Src Family Kinase Inhibitors for Cancer Therapy
Richard Jove, PhD, Director and Professor, Beckman Research Institute, City of Hope Cancer Center
4:20 Panel Discussion: What have we learned? The take home message.
4:50 End of Conference
Day 1
For more information on this conference, contact:
Margit Eder, Ph.D., Conference Director
Cambridge Healthtech Institute
Phone: 781-972-5478
E-mail: meder@healthtech.com
For Sponsor and Exhibit Information, contact:
Suzanne Carol, Business Development Manager
Cambridge Healthtech Institute
Phone: 781-972-5452
E-mail: scarroll@healthtech.com