Cambridge Healthtech Institute’s Inaugural

Small Molecules for Immunology & Oncology

Drug Discovery against Molecular Targets in Inflammation, Autoimmunity and Cancer

April 15-16, 2020



Cambridge Healthtech Institute’s Inaugural Small Molecules for Immunology & Oncology conference is a merging of our long-standing Inflammation Inhibitors meeting with our more recent Small Molecules for Cancer Immunotherapy conference in recognition of the commonalities among the drug targets in both fields from the standpoint of a medicinal chemist.

Evidence is mounting that autoimmunity/inflammation versus cancer can be considered two sides of the same coin. Inflammation arises when the immune system is overactive whereas cancer is largely a result of an underactive or subverted immune system. Hence medicinal chemists often design drugs against the same target for these seemingly opposite diseases: developing antagonists to inhibit autoimmunity/inflammation or agonists for the same molecular target to activate the immune system against cancer. We hope you can join fellow chemists at this event to share strategies, successes and challenges in discovering and optimizing drug candidates that have the potential to be orally bioavailable modulators of the immune system be it for cancer or other diseases.

Final Agenda

Wednesday, April 15

12:30 pm Registration Open

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

STING

1:30 Welcome Remarks

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

1:35 Chairperson’s Opening Remarks

Snahel Patel, PhD, Senior Director and Head, Medicinal Chemistry, Tenaya Therapeutics

1:40 UnderstandING STING in Inflammation and Cancer

Jeonghyun Ahn, PhD, Research Professor, Laboratory of Glen Barber, Department of Cell Biology, University of Miami School of Medicine

Stimulator of IFN genes (STING) is one of the innate immunity sensors activated by cytosolic DNA, such as cyclic dinucleotides (CDNs) secreted by intracellular bacteria or generated by a cellular cGAMP synthase (cGAS). While transient STING function has found to be essential for protection of the host against viral infection, chronic STING activity by self-DNA leaked from the nucleus has been implicated in causing lethal autoinflammatory diseases. I will illustrate how the molecular mechanisms of STING enable it to both, be a target for combatting inflammatory disease as well as a providing a novel therapeutic strategy for converting an immunologically “cold” tumor to “hot” by stimulating anti-tumor immune responses.

2:10 Characterization of Novel STING Ligands

Gottfried SchroederGottfried Schroeder, PhD, Senior Scientist, Department of Quantitative Biosciences, Merck Research Labs Boston

Modulation of the innate immune receptor STING is of pharmacological interest for both oncology and autoimmune indications. Binding of cyclic dinucleotide 2’3’-cGAMP to dimeric STING stabilizes a ‘lid-closed’ protein conformation, ultimately inducing interferon production. Biophysical characterization of different classes of STING ligands using surface plasmon resonance (SPR) has revealed significant differences in binding kinetics, stoichiometry and mode of action. The results of complimentary techniques further support these observed mechanistic differences.

2:40 FEATURED PRESENTATION: Discovery of STING Agonist with Systemic Anti-Tumor Response

Scott Pesiridis, PhD, Associate Fellow, Scientific Leader, Discovery Biology, GlaxoSmithKline

Medicines targeting STING are intensely pursued as innate immune modulators with potential to complement other immuno-oncology agents. While the first wave of STING agonists are derived from cyclic dinucleotides limited to intra-tumoral delivery, we discovered a small molecule dimeric ligand known as the ABZI series that is selective STING agonists with remarkable single agent efficacy upon intravenous delivery.

3:10 CETSA HT, A Powerful Assay for Small Molecule Drug Discovery

Stina Lundgren, Principal Projects Advisor, Pelago Bioscience

CAS_New3:25 Presentation to be Announced

 

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

Targeting Cell Surface Immuno/Onco-Related Proteins

4:30 Targeting av Integrins for Fibrosis

Katerina Leftheris, PhD, Vice President, Chemistry, Pliant

Av integrins are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. Targeting av integrins with small molecules has been a challenge in the drug discovery field, primarily due to limited approaches to selectivity, complex signaling mechanisms, poor ADME properties and poor translation to a clinical setting. This talk will focus on our approach to addressing these concerns, leading to in vivo active molecules that translate to human disease.

5:00 CryoEM for Drug Discovery against ‘Immuno’ Important Membrane Proteins

Seungil HanSeungil Han, PhD, Cryo-EM Lab Head, Structural & Molecular Sciences, Pfizer Global R&D

This talk will describe applications of cryo-EM to investigations of solute carrier transporter proteins to enable drug discovery. The prospects of studying large disease-relevant macromolecular complexes without having to generate single crystal are very appealing and cryo-EM is becoming a part of lead generation in more and more research departments. The introduction of direct electron detectors, the resolution and range of biological molecules amenable to single particle cryo-EM have enabled this.

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: The Chemistry of Small Molecule Immunomodulators in the Clinic

Moderator: Murali Ramachandra, PhD, CSO, Aurigene Discovery Technologies Limited

  • Single agents and combination therapies
  • Challenges with potency and selectivity
  • Drug delivery and formulation

Topic: Cryo-EM for Drug Discovery

Moderator: Seungil Han, PhD, Cryo-EM Lab Head, Structural & Molecular Sciences, Pfizer Global R&D

  • What is the bottleneck in cryo-EM?
  • Current applications
  • Future directions

Topic: Modulating STING

Moderator: Gottfried Schroeder, PhD, Senior Scientist, Department of Quantitative Biosciences, Merck Research Labs Boston

  • Distinct structural features of STING to design modulators against
  • Biologics vs. small molecule approaches for modulating STING
  • MOA and physiological considerations, possible side effects, etc.

6:15 Close of Day

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

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)

Intracellular Immuno-Targets: Kinases, Nuclear Receptors

10:40 Chairperson’s Remarks

Katerina Leftheris, PhD, Vice President, Chemistry, Pliant

10:45 Discovery and Development of BIIB068: A Selective, Potent, Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK)

Bin MaBin Ma, PhD, Senior Scientist, Medicinal Chemistry, Biogen

Covalent modification of BTK has been proven to be beneficial for cancer patients with multiple drugs on market while their safety profiles are concerned for autoimmune disease indications. A reversible non-covalent BTK inhibitor will have the promise to address this unmet need. We will report our discovery of BIIB068, an exquisitely selective, potent, reversible BTK inhibitor, together with the med chem strategy and Phase I clinical results.

11:15 Regulation of Inflammatory Cell Death Signaling by RIP Kinases

Domagoj Vucic, PhD, Principal Scientist, Early Discovery Biology, Genentech

11:45 Presentation to be Announced

12:00 pm An ROR-Gamma Inverse Agonist for the Treatment of Psoriasis

Murali RamachandraMurali Ramachandra, PhD, CEO, Aurigene Discovery Technologies Limited

This presentation will cover the discovery and development of AUR101, an ROR-gamma inverse agonist, which is currently in Phase 1 clinical trials for the treatment of psoriasis.

12:30 Session Break

12:40 Luncheon Presentation to be AnnouncedPharmablock

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced (Sponsorship Opportunity Available)

New Intracellular Immuno-Targets

2:15 Chairperson’s Remarks

Scott PesiridisScott Pesiridis, PhD, Associate Fellow, Scientific Leader, Discovery Biology, GlaxoSmithKline


2:20 Small-Molecule TEAD-Yap Covalent Antagonists

Samy MerouehSamy Meroueh, PhD, Associate Professor, Biochemistry & Molecular Biology, Indiana University

Yap1 creates a signaling hub that promotes tumor growth and immune evasion. Yap1 tightly binds to TEAD transcription factors making the development of small-molecule inhibitors challenging. Here, we report small-molecule TEAD-Yap inhibitors that form a covalent bond with a cysteine in the palmitate-binding pocket of TEADs. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, and suppressed expression of connective tissue growth factor.

2:50 Targeting Vps34 Induces a Proinflammatory Microenvironment Resulting in Tumor Growth Inhibition and Sensitization to PD-1/ PD-L1 Blockade

Jenny ViklundJenny Viklund, Director, Protein Science & Drug Design, Sprint Bioscience

New combination strategies are needed to increase therapeutic efficacy of anti-PD-1/PD-L1-based immunotherapy. Autophagy has been associated with a proinflammatory response regulating innate immunity. We found that genetic and pharmacological inhibition of the novel autophagy target Vps34 reduce tumor growth and increase the infiltration of immune cells with cytotoxic activity. Furthermore, treatment with small molecule Vps34 inhibitors (whose discovery is described in an earlier presentation on ‘FBDD’ conference track) significantly improved the efficacy of anti-PD-L1/anti-PD1 therapy.

3:20 Disrupting Tumor Metabolism: Targeting Arginase Inhibitors

Emil KuriaKose, PhD, Director, Biology, Calithera

I will provide an overview of the mechanistic rationale for arginase inhibition as an immune activating therapy. I also discuss the specific aspects of the compound that provide a viable therapeutic index in the clinical setting. Our arginase inhibitors are in Phase 1 clinical study.

3:50 Networking Refreshment Break

Encoded Library-Origin Compounds for Oncology

4:20 DEL-Enabled Discovery of Novel MoA and Structurally Unique IDO1 Inhibitors

Bing Xia, PhD, NCE Encoded Library Technologies, RD Medical Science & Technology, GlaxoSmithKline

Indoleamine 2,3-dioxogenase-1 (IDO1) is induced and activated in response to viral and bacterial infection causing a dysfunctional immune response in clearing pathogens. IDO1 inhibitors (IDO1i) have the potential to restore immune function in indications such as cancer and infection. A structurally-unique IDO1i class was discovered through the affinity selection of a novel DNA-encoded library. After additional medicinal chemistry iterations, the compound series was elaborated into potential best in class preclinical molecule.

4:50 Discovery and Application of a Novel Cell Death Mechanism in Oncology

Maria SoloveychikMaria Soloveychik, PhD, Co-Founder and CEO, SyntheX

We developed STX100, a peptide originating from an encoded library, targeting an intracellular protein-protein interaction in the homologous recombination DNA repair pathway. STX100-mediated cell killing is independent of canonical cell death mechanisms; it relies on acute calcium release from its target to elicit cell death. The mechanism translates to in vivo models, where a local delivery of STX100 and a combination of immune checkpoint blockade (ICB) agents can cure established tumors resistant to ICB therapies.

5:20 Talk Title to be Announced

Speaker to be Announced, Nuevolution

5:50 Close of Conference

* The program is subject to change without notice, due to unforeseen reason.

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Update History
2020/02/10
Agenda,Sponsor updated
2019/12/25
Agenda,Sponsor updated
2019/11/25
Sponsor updated
2019/10/31
Agenda,Sponsor updated