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メインカンファレンスプログラム 第2日目
2008年6月27日（金）
7:30 am Breakfast Workshop or Morning Coffee
EXPERIMENTAL APPROACHES
8:20 Chairperson’s Remarks
Roderick E. Hubbard, Senior Fellow, Vernalis and Professor, University of York
8:30 Bridging the Affinity Gap: Application of Label-free Methods in Fragment-based Lead Generation
Stefan Geschwindner, Ph.D., Principal Scientist and Team Leader, Protein Engineering, Global Structural Chemistry, AstraZeneca R&D Mölndal
Even so high-throughput screening (HTS) is seen as the most common approach within the drug discovery process, there remain fundamental issues that limit its scope. Fragment-based lead generation (FBLG) addresses most of those issues and is increasingly being accepted as a valuable complement to HTS. The FBLG process roughly consists of three phases and starts usually by screening small collections (100s-1000s) of low MWt compounds (150-250 Da) against the target of interest. In the following expansion phase the resulting Hits are analysed and nearest neighbours (analogues) are tested with the aim of increasing affinity and developing preliminary SAR. Finally, synthetic chemistry is applied to further derivatise and optimise the best ligands, usually supported by structure-based drug design. In that context the presentation will focus on the application of label-free methods as a tool to bridge the existing affinity gap between an conventional HTS-like assay and very sensitive methods like e.g. NMR in order to deliver decisive data on affinity and MOA of primary fragment hits and their analogues. The concept will be presented on an active drug discovery project, where FBLG was applied to find novel small-molecule inhibitors of ß-secretase (BACE), a key target for the treatment of Alzheimer’s disease.
9:00 Protonate 3D: Assignment of Protonation State and Geometry in Macromolecular StructuresPaul Labute, Ph.D., President, Chemical Computing Group Inc.
A method is presented for assigning protonation states and hydrogen atom geometry to macromolecular structures. Tautomer and ionization state (including metal ligation) are taken into account during a large scale free energy optimization. This discrete optimization is performed with a fast Unary Quadratic Optimization algorithm that can handle large systems in reasonable time. The thermodynamic theory and the results of several computational validation experiments will be presented.
9:30 Use of Mass Spectrometry to Help Drive the Design of a Drug Candidate from Inception to Development
Jennifer Nemeth, Ph.D., Principal Research Scientist, Protein Engineering, Centocor Research and Development
Mass spectrometric, as well as other analytical techniques, were applied to an early research program in Centocor’s Discovery Research Department to help characterize and drive the development of the drug candidate. The antibody-like drug, known as a MimetibodyTM, was consisted of an active peptide, linker sequence, and IgG Fc. The original construct exhibited lot-to-lot inconsistencies, and there was a great deal of variability in the in vitro activity results. Mass spectrometry was the main technique used to determine the cause for the variability in the initial construct, as well as for screening subsequence generations of the engineered MMB as it was further optimized. The current drug candidate is now approaching the final stage-gate to transfer it into Pharmaceutical Development, where preparation for toxicology and first-in-human studies would begin.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Technology Spotlight
Exploring Receptor-Flexible Docking
C.M. (Venkat) Venkatachalam, Ph.D., Fellow, Accelrys, Inc.
Experimental evidence shows that protein structures adopt varying conformations when different ligands are bound to it. Virtual high-throughput screening generally employs a single receptor structure with a wide variety of ligands. However, protein flexibility may play a vital role in the mechanism of ligand docking. We have developed a small molecule docking workflow that allows for receptor flexibility using the CHARMm force field. The extent of flexibility in the receptor binding site, as well as the movement of protein side chain atoms in response to a placed ligand, are modeled in this method. Results of ross-docking with 21 protein-ligand complexes comprising eight protein classes show that introducing receptor flexibility during docking significantly improves docking accuracy. The method can be easily extended to consider loop conformation changes as well. Lastly, we will also present complementary results from the use of pharmacophores to sample receptor flexibility.
STRUCTURE-BASED MODELING OF GPCRs
11:00 5HT1A and 5HT6 Ligating Drugs from Computer Model to Clinical Trial
Sharon Shacham, Ph.D., Vice President, Drug Development, EPIX Pharmaceuticals
EPIX Pharmaceuticals has applied its unique structure-based approach based on the PREDICT technology and other methodologies to develop two novel, highly selective serotonin receptor-targeted drugs in clinical development for the treatment of Alzheimer’s disease and other CNS disorders. PRX-07034 is a potent (Ki = 4-8nM) serotonin subtype 6 (5-HT6) receptor antagonist in early clinical trials. Preclinical studies have demonstrated that PRX-07034 significantly improved cognitive functioning in a variety of learning and memory models, including scopolamine-induced memory deficits, age-induced memory deficits, working memory and executive function/cognitive flexibility. PRX-07034 also enhanced the efficacy of donepezil (Aricept®) in a preclinical test of recognition memory. 5-HT6 receptor antagonists have been shown to modulate several neurotransmitter systems, including acetylcholine, involved in learning and memory. A 28-day Phase 1 multiple ascending dose clinical trial of PRX-07034 was recently completed. The study was designed to assess the safety and tolerability of PRX-07034 in obese, otherwise healthy volunteers, as 5-HT6 antagonism has also been proposed as a treatment for obesity. Cognitive functioning was assessed as a secondary endpoint using the CogScreenTM test battery. Results of the study will be presented. A second drug candidate, PRX-00023, is a selective 5-HT1 agonist (Ki = 10nM) is currently trials for major depressive disorder and anxiety. Based on the anti-depressant efficacy, a double-blind, randomized, placebo-controlled study is underway in patients with depression and concurrent anxiety. Results are expected in early 2008.
CASE STUDIES
11:30 The Design and Synthesis of Novel Second Generation HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Thomas J. Tucker, Ph.D., Senior Research Fellow, Dept. of Medicinal Chemistry, Merck Research Laboratories
Since their discovery in the early 1990’s, Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active anti-retroviral therapy (HAART). There are currently three commercially available NNRTIs : efavirenz, nevirapine, and delavirdine. The use of efavirenz and nevirapine has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is however a critical issue with the emergence of clinical resistance and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. The NNRTI program at Merck has been directed towards finding novel NNRTIs that possess high levels of antiviral potency against key clinically observed mutant viruses. Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. This presentation will highlight the design and development of this series of compounds and will describe the progression of these compounds from early lead structures to development candidates.
12:00 pm Luncheon Technology Workshop or Lunch on Your Own
(Sponsorship Available. Contact Katelin Fitzgerald at kfitzgerald@healthtech.com or 781.972.5458)
1:25 Chairperson’s Remarks
1:30 Structure Based Drug Design of HIV-1 Reverse Transcriptase Inhibitors
Christopher Phillips, Ph.D., Senior Principal Scientist, Exploratory Medicinal Sciences, Pfizer Global Research and Development
HIV-1 reverse transcriptase (RT), a major target for anti-HIV drugs, has been extensively studied crystallographically. The overall heterodimeric structure has been defined and numerous inhibitor complex structures described]. Three non-nucleoside RT inhibitors (NNRTIs), namely efavirenz, nevirapine and delavirdine, are approved as key components of Highly Active Antireteroviral Therapy (HAART) combinations. However each of these inhibitors are susceptible to mutations in RT leading to drug resistance. The novel NNRTi UK-453061 is active against a broad range of drug-resistant viral strains. We report findings from some 50 plus crystal structures of different NNRTi enzyme complexes determined as part of a structure based design program. The complexes with UK-453061 itself, close analogues and representatives of several more diverse chemical series including both novel “in-house” and literature compounds are described. Structural determinates of broad mutant profile, series SAR, and examples of structure based design approaches used are discussed.
2:00 Technology Spotlight (Sponsorship Available)
2:15 Networking Refreshment Break, Poster and Exhibit Viewing
3:00 From Virtual Screening to Clinic: Discovery of Cevoglitazar
T. R. Vedananda, Ph.D., Program Head, Diabetes & Metabolism, Novartis
The discovery of Cevoglitazar as a potent PPARa/g dual agonist was a combined effort of virtual screening of 3D databases and structure-based drug design. Computer aided molecular design was initiated by examining known ligand bound PPARg X-ray structures. To develop a pharmacophore model for database searching, observed protein-ligand interactions were simplified to an essential set of three hydrogen bonds, identifying three acceptor atoms as the core components of the pharmacophore model. Using Unity module of Sybyl, searches were performed on internal and external 3D databases covering nearly 1.3 million structures. All 4021 hits were visually inspected and those which could not be transformed into potential synthetic targets were eliminated. For the surviving hits, structural modifications were facilitated by docking calculations. Subsequent structure-based elaboration of most advanced leads led to the identification of Cevoglitazar as a potent PPARa/g dual agonist.
3:30 The Discovery of OSI-906: A Novel, Potent, Orally Bioavailable Imidazopyrazine-derived Insulin-like Growth Factor-I Receptor (IGF-1R) Inhibitor with Antitumor Activity
Mark Mulvihill, Ph.D., Associate Director of Chemistry, Oncology, OSI Pharmaceuticals
The insulin-like growth factor receptor (IGF-1R) is a tetrameric transmembrane tyrosine kinase which has been implicated as a key driver in certain forms of solid tumors and hematologic neoplasias. Activation of IGF-1R and its intracellular substrates leads to signal transduction processes which operate through both the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways, synergizing to promote cellular proliferation, inhibit apoptosis, and increase cell survival. We discovered a novel series of 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines as IGF-1R tyrosine kinase inhibitors which progressed from an earlier benzyloxyphenyl-derived series to a bioactive conformationally constrained 2-phenylquinolinyl series via structure-based efforts derived from IGF-1R and IR x-ray co-crystal structures with select imidazopyrazines. From this series, cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-meth yl-cyclobutanol (OSI-906) emerged as the best-in-series and is currently under evaluation in Phase I clinical trials. Key in vitro and in vivo preclinical biological results which supported the IND-nomination and progression of OSI-906 into clinical trials are: inhibition of ligand-stimulated autophosphorylation of IGF-1R and downstream pathways in IGF-II/IGF-IR autocrine loop-driven GEO colon carcinoma cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; solid correlation between pharmacokinetic and pharmacodynamic effects; antitumor activity in Colo-205 and GEO colon carcinoma xenograft models as a single agent and in combination with small molecule EGFR inhibitor, erlotinib; and once-a-day vs. twice-a-day dosing effects on plasma glucose levels.
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4:00 Structure-based Discovery of Clinical Candidates for Hsp90
Roderick E. Hubbard, Senior Fellow, Vernalis and Professor, University of York
We have developed and applied a range of structure-based methods in the discovery and optimisation of compounds that inhibit the oncology target, Hsp90. I will describe the application of virtual screening and fragment-based discovery methods as well as the details of the structure-guided medicinal chemistry that has resulted in a compound entering Phase I clinical trials.
4:30 Closing Remarks
4:45 Close of Conference
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