Cambridge Healthtech Institute’s 13th Annual
Targeting PPIs and Nucleic Acid Complexes for Therapeutic Interventions
NEW DATES - AUGUST 26-27, 2020
More examples in medical research are now arising about diseases that can be addressed by disrupting or modifying complexes of proteins that aberrantly interact with one another. Such protein-protein interaction (PPI) complexes can be considered a type
of drug target. PPI targets are different from traditional drug targets that comprise of a single protein, more specifically an enzyme, whose function is targeted for reduction by a chemical inhibitor. For the medicinal chemist whose role is to discover,
design or optimize compounds with therapeutic potential, PPIs are expanding what can be ‘drugged or targeted’ by them. However, the ‘flat and large’ interacting surfaces of PPIs make them less amenable to the typical ‘groove
and ball’ inhibitor design strategy for enzymes. Luckily, advances in biophysical techniques such as nuclear magnetic resonance (NMR), surface plasmon resonance (SPR) that enable rapid detection of bi-molecular interactions without an enzymatic
readout, have aided progress in finding new drug leads against PPIs. At CHI’s 13th Annual Protein-Protein Interactions conference, join fellow discovery chemists to share stories and discuss best practices in this new area of disease-relevant
space that is rapidly becoming more accessible.
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Wednesday, April 15
12:30 pm Registration Open
12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
1:30 Welcome Remarks
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
1:35 Chairperson’s Opening Remarks
Samantha Allen, PhD, Principal Scientist, Discovery Sciences, Janssen R&D
1:40 FEATURED PRESENTATION: Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer
Andrew Petros, PhD, Senior Principal Research Scientist, Protein & Assay Sciences, AbbVie
Apolipoprotein E is a lipid carrier protein that exists as three isoforms denoted apoE2, apoE3, and apoE4 with the apoE4 protein exhibiting reduced thermal stability compared to apoE2 and apoE3. Genome-wide association studies indicate that the possession
of two E4 alleles is a strong genetic risk factor for late-onset Alzheimer’s disease. NMR-based screening on the N-terminal domain of apoE4 identified a fragment binder that was subsequently, using SBDD, elaborated into a single-digit micromolar
2:10 Using cryo-EM to Understand RET Receptor Tyrosine Kinase Activation by Neurturin and GFRα2
Jenny Sandmark, PhD, Associate Principal Scientist, Drug Discovery, AstraZeneca R&D
RET signalling is implicated in a number of disease states. Overactivity may result in cancer, but stimulation of the system is being considered as treatment for neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. We have
determined the cryo-EM structure of the hexameric signalling complex formed between RET, the NRTN ligand and GFRα2 co-receptor. The structure highlights the importance of the cysteine-rich domain of RET for the complex assembly and signalling.
2:40 Inhibitors of Sec61 as Novel Anti-Cancer Therapeutics
Dustin McMinn, PhD, Senior Director, Head of Chemistry, Kezar Life Sciences
Post-translational functionalization of most secreted and transmembrane proteins requires co-translational translocation to the ER through Sec61. Translocation is negotiated by protein interactions between Sec61 and unique signal sequences specific
to each translating protein. Disruption of these interactions in specific or multi-signal sequence fashion presents an opportunity to modulate protein homeostasis toward therapeutic benefit. Development of signal and multi-signal sequence selective
Sec61 inhibitors as novel anti-cancer agents will be discussed.
3:10 Sponsored Presentation (Opportunity Available)
3:40 Refreshment Break and Book Signing in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
4:30 Late Breaking Presentation: Small-Molecule Ral GTPase Covalent Inhibitors
Samy Meroueh, PhD, Associate Professor, Biochemistry & Molecular Biology, Indiana University
5:00 Leveraging Viral Protein-Protein Interactions to Generate Inhibitors of BK and JC Polyomavirus in Early-Stage Drug Discovery
Charles Wartchow, PhD, Senior Investigator, Global Discovery Chemistry, Novartis Institutes for
BK and JC viruses reactivate during immunosuppression, resulting in nephropathy or multifocal leukoencephalopathy, respectively. To establish anti-viral MOAs involving viral protein-protein interactions, we examined capsid proteins VP1 and VP2 and
identified a VP2-derived peptide with anti-viral activity. With biophysical and biochemical screens, we identified hits that bind VP1 and these compounds inhibit a VP1 and VP2 interaction in vitro.
5:30 Breakout Discussions - View All Breakouts
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: Biophysical Hit Assessment for PPI Targets
Moderator: Mary Harner, PhD, Research Investigator II, Mechanistic Biochemistry, Bristol-Myers Squibb R&D
- Molecular properties: eliminating false positive hits
- Target engagement technology selection 101: TSA, NMR, MST, SPR, other
- Improving confidence by combining technologies
- Importance of controls: reference molecules, specificity targets
- Delineating hits: mechanism of binding, binding site elucidation
Topic: Degradation-Inducing Therapeutics
Moderator: Philip Chamberlain, DPhil, Director, Structural and Chemical Biology, Celgene
- Various ‘molecular glues’ for targeted protein degradation strategies: SNIPER, cereblon, PROTACS, degronomid
- Which technique to try first?
- Hurdles to their therapeutic potential
- Any stories or difficulties to share?
Topic: Methods to Identify PPI Modulators
Moderator: Samantha J. Allen, PhD, Principal Scientist, Screening, Janssen R&D LLC
- Biochemical, biophysical and cell-based screening approaches
- Library selection
- Understanding ligandability
6:15 Close of Day
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6:30 Dinner Short Courses
Thursday, April 16
8:00 am Breakfast Plenary Technology Spotlight (Sponsorship Opportunity Available) or Morning Coffee
8:45 Plenary Welcome Remarks from Event Director with Poster Finalists Announced
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
8:55 Plenary Keynote Introduction (Sponsorship Opportunity Available)
9:00 PLENARY KEYNOTE:
Phil Baran, PhD, Professor, Department of Chemistry, Scripps Research
There can be no more noble undertaking than the invention of medicines. Chemists that make up the engine of drug discovery are facing incredible pressure to do more with less in a highly restrictive and regulated process that is destined for failure
more than 95% of the time. How can academic chemists working on natural products help these heroes of drug discovery – those in the pharmaceutical industry? With selected examples from our lab and others, this talk will focus on that question
highlighting interesting findings in fundamental chemistry and new approaches to scalable chemical synthesis.
9:45 Coffee Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
10:40 Chairperson’s Remarks
Kevin Lumb, PhD, Senior Director, Lead Discovery, Janssen R&D LLC
10:45 Covalent Fragment-Based Drug Discovery: KRAS and Beyond
Daniel Erlanson, PhD, Vice President, Chemistry, Frontier Medicines
Fragment-based drug discovery (FBDD) has delivered roughly 50 drugs into the clinic, three of which have been approved. The protein KRAS has been intensively studied as an oncology target for decades, but has largely resisted drug discovery efforts.
This presentation will describe how FBDD has led to novel, irreversible small molecule inhibitors of the oncogenic G12C mutant form of KRAS.
11:15 Translating Frontier Oncology Targets to Outsmart Cancer
James Aggen, PhD, Senior Director, Medicinal Chemistry, Revolution Medicines
We have developed tri-complex inhibitors of KRASG12C(ON) that selectively drive formation of KRASG12C-inhibitor-CypA ternary complexes through significant non-covalent interactions combined with a druglike cysteine-targeted warhead to potently and
irreversibly inhibit KRASG12C(ON). In cellular models, KRASG12C(ON) inhibitors show differentiation to first generation KRASG12C(OFF) inhibitors in cancer cell lines bearing KRASG12C mutations and drive dose-dependent tumor regressions in a KRASG12C
NSCLC xenograft mouse model.
11:45 Fragment Screening by Weak Affinity Chromatography (WAC) Against PPIs
Björn Walse, CEO, SARomics Biostructures/Red Glead Discovery
The advantage of WAC™ for FBS are the detection of weak binders by screening fragments at low concentrations (<5 μM) and its immediate ranking of hits. Here we compare the result of a WAC™ screen towards SMARCA4 with results
from fragment screens using other techniques
12:00 pm Targeting KRAS Directly with Novel Drug Discovery Efforts at the NCI RAS Initiative
Dominic Esposito, PhD, Director, Protein Expression Laboratory, Frederick National Laboratory
for Cancer Research (FNLCR)
The NCI RAS Initiative, led by scientific director, Frank McCormick of UCSF, combines novel drug discovery approaches (covalent tethering, computational modeling, and structure-guided fragment-based screening) to identify new compounds that directly
target KRAS and its oncogenic mutants. These techniques provide a potential set of new targets in RAS drug discovery which have not yet been fully explored and will be discussed in this presentation.
12:30 Session Break
12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced (Sponsorship Opportunity Available)
2:15 Chairperson’s Remarks
Charles Wartchow, PhD, Senior Investigator, Global Discovery Chemistry, Novartis Institutes for Biomedical Research
2:20 Targeting Mutant KRAS by Direct and Indirect Approaches
Michael Gmachl, PhD, Principal Scientist, New Therapeutic Concepts, Boehringer-Ingelheim
KRAS is the most frequently mutated oncogene. Boehringer-Ingelheim has developed small molecule inhibitors binding and blocking KRAS independently of the mutation and activation status as well as an NCE targeting SOS1, an exchange factor, necessary
for the conversion of inactive to active KRAS. The features of both of these molecules in vitro as well as in vivo will be discussed.
2:50 Discovery and Early Development of MRTX849, a Selective, Covalent Inhibitor of KRAS G12C
Matt Marx, Vice President, Drug Discovery, Mirati Therapeutics
MRTX849 is an irreversible, covalent inhibitor of KRASG12C currently undergoing clinical investigation in cancer patients with this mutation. This compound binds in the switch-II pocket of GDP-bound KRAS, locking the protein in the inactive state.
Previously, we have described the structure-based design of the in vivo tool compound MRTX1257, and this talk will highlight the liabilities of this tool molecule and the strategies utilized for its final optimization
3:20 High-Throughput Mass Spectrometric Analysis of Covalent Protein-Inhibitor Adducts for the Discovery of KRAS G12C Inhibitors
John McCarter, PhD, Head, Affinity Screening Technologies, Amgen
A high-throughput MS platform was used to accurately detect and quantitate different covalent modifications of proteins including KRAS G12C which contain one or more reactive cysteines, lysines, or other nucleophilic residues. We employed the Agilent
RapidFire system to rapidly quantitate the extent of covalent protein inhibitor adduct formation by MS for several proteins including KRAS G12C and human serum albumin. We used this approach to screen large numbers of potential covalent inhibitors
in an automated fashion and to test medicinal chemistry compounds as part of a regular lead optimization cycle for KRAS G12C.
3:50 Networking Refreshment Break
4:20 Design of Small Molecule Allosteric Reversible Inhibitors of K-Ras with Antitumor Activity
Juan Perez, PhD, Professor, Molecular and Industrial Biotechnology, Polytechnic University of Barcelona
We disclose the design and synthesis of a novel series of small molecule inhibitors that reversibly bind to K-Ras at the nanomolar scale. Tested in a xenograft model for non-small-cell lung cancer (NCI-H358) in daily doses of 0.1 mg/kg ip, these compounds
prevent tumor growth without any significant loss of body weight and do not exert any obvious toxic effect. These results suggest that it is possible to design reversible allosteric inhibitors of the K-Ras, opening the door for a new class of
4:50 Discovery of First-in-Class Allosteric Inhibitors of BAX
Evris Gavathiotis, PhD, Professor, Biochemistry, Albert Einstein College of Medicine
The BCL-2 family protein BAX is a critical effector of apoptotic cell death in response to a diverse range of stimuli. Efforts to rationally target BAX have been elusive, despite the promising therapeutic potential for a host of diseases. My presentation
will discuss the use of NMR and biochemical methods to screen and characterize the first inhibitors of inactive BAX that bind to a previously unrecognized allosteric pocket. Structure-based and mechanistic insights, cell-based and preclinical
in vivo studies with this challenging PPI target will be discussed
5:20 Targeting Regulatory Protein-Protein Interactions of Calcium-handling Enzymes for Drug Discovery
Russell Dahl, PhD, CEO, Neurodon Corporation
Disruption of intracellular calcium ion homeostasis leads to the unfolded-protein response and endoplasmic reticulum stress. These phenomena are recognized as causal features of major diseases such as diabetes and neurodegeneration. Recent observations
suggest that these conditions initiate pro-inflammatory pathways that are fundamental to the pathogenesis of these diseases. Herein we describe the use of FRET screening techniques for the discovery and optimization of small molecule calcium-handling
modulators and their development to deliver drug candidates for these diseases.
5:50 Close of Conference
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