Cambridge Healthtech Institute’s 13th Annual

Protein-Protein Interactions
( 蛋白質交互作用 )

Targeting PPIs and Nucleic Acid Complexes for Therapeutic Interventions

2020年4月15-16日



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.

Final Agenda

4月15日(三)

12:30 pm Registration Open

12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

New PPI Targets

1:30 Welcome Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Samantha AllenSamantha 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 stabilizer.

2:10 Using cryo-EM to Understand RET Receptor Tyrosine Kinase Activation by Neurturin and GFRα2

Jenny SandmarkJenny 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 McMinnDustin 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 CO-PRESENTATION: E3scan™ Ligand Binding Assay Platform and EFC Biosensor Cell Lines for Targeted Protein Degradation and PROTAC Discovery

Lamerdin JaneJane Lamerdin, PhD, Director, Research & Development, Eurofins Discovery


Cohen_Katsenelson_KsenyaKsenya Cohen Katsenelson, PhD, Senior Scientist Group Leader, San Diego R&D, Eurofins Discovery

Eurofins Discovery will present how the novel E3scan technology has been applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP. We will also present how engineered biosensor cell lines employing gene editing with CRISPR/Cas9 and our well-established EFC technology will enable sensitive quantitation of PROTAC-mediated degradation of the target of interest in physiologically relevant cell models using a homogeneous assay format.

3:40 Refreshment Break and Book Signing in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

Infectious Disease Targets

4:30 Identification of a New Class of HBV Capsid Assembly Modulator

Scott Kuduk, PhD, Scientific Director, Discovery Chemistry, Novira/J&J

Chronic Hepatitis B virus infection is a common cause of severe liver disease necessitating the identification of new antiviral mechanisms to improve treatment outcomes. The HBV core capsid protein has multiple essential functions in the HBV life cycle enabling chronic HBV infection. HBV capsid assembly modulators (CAMs) have demonstrated proof of mechanism in early clinical trials. This presentation describes a completely novel series of pyrazolo piperidine HBV capsid assembly modulators.

5:00 Leveraging Viral Protein-Protein Interactions to Generate Inhibitors of BK and JC Polyomavirus in Early-Stage Drug Discovery

Charles WartchowCharles Wartchow, PhD, Senior Investigator, Global Discovery Chemistry, Novartis Institutes for Biomedical Research

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

6:30 Dinner Short Courses

4月16日(四)

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

Speaker to be Announced, LabTwin


9:00 PLENARY KEYNOTE:

baranPphilTranslational Chemistry

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)

Targeting KRAS: Preclinical Compounds

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

Adrian Gill, PhD, Vice President, Medicinal Chemistry & CMC, 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 Presentation to be Announced

 

 

12:00 pm Targeting KRAS Directly with Novel Drug Discovery Efforts at the NCI RAS Initiative

Dominic EspositoDominic 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)

Targeting KRAS: Compounds in the Clinic

2:15 Chairperson’s Remarks

Charles WartchowCharles 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 MarxMatt 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 to MRTX849.

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

More RAS and Beyond

4:20 Design of Small Molecule Allosteric Reversible Inhibitors of K-Ras with Antitumor Activity

Juan PerezJuan 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 therapeutic agents.

4:50 Discovery of First-in-Class Allosteric Inhibitors of BAX

Evris GavathiotisEvris 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 DahlRussell 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

* 活動內容有可能不事先告知作更動及調整。

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