Targeting the non-catalytic site of protein-protein interactions (PPIs) with small molecules has enabled drug discovery to move beyond the typical enzyme targets such as proteases and kinases and address disease-state relevant regulatory complexes of biological processes such as intracellular signal transduction, transcription, immuno-modulation, epigenetic modifications and protein stability. However targeting PPIs pose unique challenges because the targets’ structure (an interaction site between two proteins) is often not known and is usually a larger area with different physico-chemical properties than a ‘catalytic site’. Cambridge Healthtech Institute’s seventh annual Protein-Protein Interactions meeting will highlight the different disease areas where targeting PPIs is showing promise and will bring colleagues together to discuss lead optimization challenges for the medicinal chemist. Hear case studies of PPI-targeted compounds that are progressing in drug development or not, with a focus on the kinds of roadblocks the compounds encountered.
The Drug Discovery Chemistry conference offers a compact, dynamic event over
Kenneth D., Director, FLAMMA
three days that allows the scientific community an excellent opportunity to stay aware of current trends.
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
David Fry, Ph.D.,Vice President, Protein Chemistry, The Chemistry Research Solution (TCRS), LLC
» 8:10 Featured Presentation: Treating Cancer by Disrupting Protein-Protein Interactions
Kurt Deshayes, Ph.D., Senior Scientist, Early Discovery Biochemistry, Genentech
The pro-survival IAP and BCL-2 proteins represent highly attractive PPI targets since their over-expression is associated with tumor progression and maintenance. We describe the discovery of completely novel series of small molecules that selectively target the IAP and select members of the BCL-2 proteins (BCL-2 and BCL-XL). Our work, guided by extensive structural information and supported by biochemical studies, illustrates the progression from initial lead to clinical candidate.
8:40 Discovery of Potent and Selective Piperidinone Inhibitors of the MDM2-p53 Interaction
Daqing Sun, Ph.D., Principal Scientist, Medicinal Chemistry, Amgen
This presentation will describe a successful approach for designing new scaffolds of MDM2 inhibitors based on the binding mode of known inhibitors with MDM2 protein. Through a combination of X-ray crystallography, molecular modeling, and iterative medicinal chemistry, we discovered highly potent, selective MDM2 inhibitors with excellent pharmacokinetic properties and in vivo anti-tumor activity in SJSA-1 osteo-sarcoma xenograft models.
9:10 The Design and Synthesis of A-Helix Mimetics as PPI Inhibitors
Roman Kombarov, Ph.D., Project Manager, ASINEX
Protein-Protein interactions have great potential as therapeutic targets but are currently one of the most challenging areas in drug discovery. Through extensive research, Asinex has identified privileged structures which are effective mimics of protein secondary structural elements. In our talk, we present a chemical platform for the efficient design of novel alpha-helix mimetics as core structures decorated with poly-substituted hydrophobic substituents. These structures have the correct geometry and substitution characteristics to align the requisite functional groups in three dimensions; these structures are, in turn, are able to disrupt key elements of the PPI interface.
9:40 Coffee Break
10:05 Fragments for Tough Targets?
Roderick Hubbard, Ph.D., Senior Fellow, Research & Development, Vernalis; Professor, University of York
Fragments are an effective approach to initiate structure-based drug discovery for conventional targets such as kinases and other enzymes. In principle, the methods should also provide an important opportunity for targeting more challenging targets, such as protein-protein interactions. I will review progress in this area. As well as summarizing recent successes for targets such as Bcl-2 and Pin1, I will highlight the technical and conceptual challenges that remain.
10:35 Allosteric Regulators Targeting Higher-Order Proteasome Assemblies in the Treatment of Cancer
Maria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, University of Texas Health Science Center at San Antonio
The proteasome is an essential human protease. Competitive inhibitors targeting proteasome’s active sites are used to treat blood cancers, however they do not perform well with other cancers. Our novel small-molecule compounds binding to allosteric sites disrupt functional integrity of the catalytic core proteasome and its interactions with protein regulatory modules. The compounds work alone or in synergy with established competitive drugs and promise to provide access to treatment of solid cancers.
11:05 Direct Inhibition of β-Catenin with Small Molecules
Elmar Nurmemmedov, Ph.D., Scientist, Molecular Experimental Medicine, The Scripps Research Institute
β-catenin is an attractive therapeutic drug target for combating various cancers. We have employed a robust screening method against four allosteric sites (TCF4-, BCL9-binding sites, and two novel sites) on β-catenin. I will present significant findings of our drug development efforts, with potential therapeutic applications for treatment of various cancers.
11:35 Luncheon Presentation: DNA-Encoded Chemistry: A New Approach to PPI and other Difficult Targets
Anthony D. Keefe, Ph.D., Senior Director, Lead Discovery, X-Chem Inc.
X-Chem Inc. operates a proprietary drug-discovery technology using its library of 100 Billion on-DNA small-molecules. Members of this library that inhibit therapeutic targets may be identified by affinity-mediated selection for target-binding followed by sequencing of the associated oligonucleotide tags, re-synthesis off-DNA and confirmation by biochemical assay. An overview of the technology will be presented along with examples of successful programs for difficult targets such as protein-protein interaction inhibitors, ubiquitin ligase, antibacterial and epigenetic targets.
12:05 pm Session Break
1:15 Chairperson’s Remarks (Sponsorship Opportunity Available)
1:20 Allosteric Inhibitors of the Heat Shock Protein 70 (Hsp70) Complex
Jason E. Gestwicki, Ph.D., Associate Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco
Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein homeostasis. Hsp70 is assisted by co-chaperones, which bind Hsp70 and shape its activities. Our strategy is to screen for molecules that control the protein-protein interactions (PPIs) between Hsp70 and its critical co-chaperones. Using reconstituted multi-protein complexes, we have identified compounds that target PPIs in this system.
1:50 Talk Title to be Announced
Lee D. Fader, Ph.D., Principal Scientist, Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc.
2:20 Sponsored Presentation
Speaker to be Announced
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
3:20 Novel Small Molecular Ligands of KEAP1 Induce Protective NRF2-Dependent Anti-Inflammatory Responses in Neurodegenerative Models
Aleksey Kazantsev, Ph.D., Associate Professor, Neurology, Harvard Medical School and Massachusetts General Hospital
The study identified a novel compounds, which induces canonical NRF2-dependent responses and are protective in Parkinson’s and Huntington’s disease models. In accord with the known anti-inflammatory effects of NRF2 activation, compounds potently repress an expression of inflammatory markers in activated microglial cells, macrocytes and in mouse brain. Reversible compound binding to the NRF2 inhibitor, KEAP1, was identified by a docking model and binding confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway.
3:50 Disrupting NRF2 and Keap1 Protein Interaction with Non-Covalent Inhibitors
Laura Silvian, Ph.D., Principal Scientist, Physical Biochemistry, Biogen Idec
Keap1 binds to the Nrf2 transcription factor to enable its ubiquitination; blocking this interaction would upregulate genes that protect against oxidative stress. Cell-active compounds that modify cysteines in Keap1 effect the Nrf2-dependent pathway. We have identified and characterized non-covalent compounds that bind to the Keap1 Kelch-DC domain and block Nrf2 binding. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side effects due to non-specific cysteine modification.
4:20 Session Break
4:30 Plenary Keynote Presentation: Drug Discovery for Challenging Targets
James Wells, Ph.D., Professor, Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California San Francisco
I will present work from our lab for two classes of challenging targets: protein-protein interfaces and novel allosteric sites, both to activate and inhibit protein function. We use a site-directed fragment-based discovery method, called Tethering, coupled to HTS approaches that are well-suited to probing these challenging surfaces. These approaches have led to the discovery of potent and selective compounds and some with surprising properties that will be discussed.
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
7:30 am CONTINENTAL BREAKFAST and 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: Allosteric Approaches to PPIs
Maria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, University of Texas Health Science Center at San Antonio
Lee D. Fader, Ph.D., Principal Scientist, Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc
• Is there a reason to go allosteric?
• Are allosterics easy to detect via screening?
• Screening issues: structural readouts vs biological activity readouts
• PPI v. phenotypic screens… where should we start first?
Topic: Small Solutions for Large Problems: Fragment and PPIs
Moderator: Edward R. Zartler, Ph.D., President & CSO, Quantum Tessera Consulting
• Fragment Library Composition for PPIs
• Hit Expansion Approaches for PPIs
• Are PPIs a “solved” problem?
Topic: Bigger Solutions for Interesting Problems: Peptides and Macrocyclics for Intracellular PPIs
Moderator: Julio Camarero, Ph.D., Associate Professor, Pharmacology and Pharmaceutical Sciences & Chemistry, University of Southern California
• Can larger molecules really get at intracellular interactions?
• Advantages over small molecules
• Design issues
8:40 Chairperson’s Remarks
Edward R. Zartler, Ph.D., President & CSO, Quantum Tessera Consulting
8:45 Small Molecule Disruptors of the GK-GKRP Interaction
Kate Ashton, Ph.D., Senior Scientist, Medicinal Chemistry, Amgen, Inc.
Targeting the GK-GKRP pathway represents a novel approach to GK-mediated glucose metabolism. Since the kinetic parameters of the GK enzyme remain unchanged, the hypoglycemic risk is greatly reduced. We observed robust glucose lowering in animal models of diabetes, with no incidence of hypoglycemia. In addition, the novelty of targeting the protein-protein interaction of GK-GKRP using structure-based drug design will be of broad interest to scientists outside of the field of metabolic disorders.
9:15 Aromatic Amino Acids: Privileged Side-Chains For Protein-Protein Interaction Inhibitor Discovery
William Pomerantz, PhD., Assistant Professor, Department of Chemistry, University of Minnesota
Given that transcription factors represent a major class of potential drug targets, our proposed 19F NMR approach to study protein-ligand interactions could significantly increase the repertoire of new targets and thereby open up new avenues for drug/probe discovery. Here we lay the framework for our ligand discovery goals using fluorinated transcription factor PPI domains, showing high incorporation (>90%) of all three fluorinated aromatic amino acids into two different proteins. We determine optimal labeling for developing a sensitive and structure-based method for ligand discovery. We characterize the binding footprints of known ligands and demonstrate our approach in a 500 compound small molecule fragment screen. Finally, using circular dichroism, fluorescence polarization, and x-ray crystallography, we demonstrate the non-perturbing nature of fluorine when placed on aromatic amino acids at PPI interfaces. 9:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:30 Targeting Intracellular Protein-Protein Interactions with Engineered Cyclotides
Julio Camarero, Ph.D., Associate Professor, Pharmacology and Pharmaceutical Sciences & Chemistry, University of Southern California
Cyclotides are emerging as frameworks for design of peptide-based diagnostic and therapeutic compounds. They are large plant-derived backbone-cyclized polypeptides, 28-37 amino acids long. They share a disulfide-stabilized core characterized by an unusual knot. Cyclotides, in contrast to other circular poylpeptides, have a well-defined three-dimensional structure. The main features of cyclotides are a remarkable stability due to the cystine knot, a small size making them readily accessible to chemical synthesis, and an excellent tolerance to sequence variations.
11:00 How to Discover New Chemical Matter for PPIs: A New Approach to Protein-Ligand Binding From the Perspective of Water
José Duca, Ph.D., Head, CADD Cambridge, Novartis Institutes for BioMedical Research, Inc.
This presentation will cover prospective and retrospective examples on drug design efforts applied to PPIs and other relevant protein-ligand systems. We have applied our new ligand-binding concepts to all aspects of drug discovery, including hit finding, de novo design and lead optimization. Our model takes into account the intra- and inter-solute interactions that occur indirectly via perturbation of the aqueous medium. Our new binding ideas have immediate implications for drug discovery, as the solvation structure can be “reverse engineered” into ligand designs and ligand efficiency can redefined by the number/quality of H-bonds gained per ligand atom when water is transferred in or out of binding sites.
11:30 Fragment-Based Approach towards Inhibitors of the TPX2 - Importin-a Protein-Protein Interaction
Rhian Holvey, Ph.D., Postdoc, Department of Chemistry, University of Cambridge
TPX2-importin-a represents a promising anti-mitotic oncology target for which cancer cells have an increased reliance on over normal cells. We have identified fragments that bind this interaction representing the first compounds to show specificity between the two sites of importin-a. The ongoing development of these compounds has shown new information about the target interaction and helped in the development of more potent inhibitors.
12:00 pm Close of Track
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