Cambridge Healthtech Instituteの第4回年次会議
Small Molecule Immuno-Modulators
2023年4月11 - 12日
Registration and Morning Coffee7:00 am
Welcome Remarks8:00 am
INHIBITING KINASES AND GPCRs FOR IMMUNO-ONCOLOGY
Selectively Inhibiting Kinase HPK1 for Immuno-Oncology
HPK1 has long been of interest as a potential pharmacological target for immune therapy because of its central role in negatively regulating T cell function. The development of a small molecule HPK1 inhibitor remains challenging because of the need for high specificity relative to other kinases that are required for efficient immune cell activation. We will present our efforts at generating selective HPK1 inhibitors to enhance the anti-tumor immune response.
Evolution of HPK1 Clinical Candidate GRC54276: The Journey, Challenges, and Solutions
HPK1 negatively regulates T & B cell signaling. Our initial HPK1 inhibitor demonstrated a modest TPP. Dissatisfied, we renewed our efforts with new chemotype designs & refined animal models. Our second-generation candidate showed excellent in vitro, immunological & safety profiles. We observed good in vivo efficacy, both as a single agent and with immune checkpoint inhibitors. GRC54276 is progressing through a multi-center, Phase I clinical trial in patients with solid tumors.
FLX475: A Potent and Selective CCR4 Antagonist to Modulate Regulatory T cells in the Tumor Micro-Environment
High levels of Regulatory T cells (Treg) accumulation in the tumor micro-environment (TME) have been shown to dampen the antitumor immune response and lead to poor prognosis in patients with various types of cancers. Treg are recruited to the TME through selective interactions of the chemokine receptor CCR4 and chemokines CCL17 and CCL22. The discovery and early clinical development of FLX475, a potent and selective CCR4 antagonist will be described.
ASP2453 is a KRASG12C inhibitor. Preclinical data suggests impressive efficacy yet it was unclear if it would show a more favorable clinical response compared to competitors. A QSP model linked to tumor growth in patients with NSCLC predicted ASP2453 exhibits greater clinical response than AMG 510, supporting potential differentiation and critical thinking for clinical trials. In some instances, pre-built TPD models can be used to more expeditiously assess TPD strategies targeting KRAS.
Networking Coffee Break10:10 am
TARGETING THE TUMOR MICROENVIRONMENT
FEATURED PRESENTATION: Discovery of Etrumandenant: A Potent Dual Adenosine Receptor Antagonist for Cancer Immunotherapy
Extracellular adenosine frequently creates an immunosuppressed tumor microenvironment by activating the G protein-coupled A2a and A2b receptors of intratumoral immune cells. Etrumadenant, a novel, selective, and non-brain penetrant small molecule dual A2aR/A2bR antagonist, potently blocks the immunosuppressive effects of high concentrations of adenosine in the tumor microenvironment. I present the design, characterization, and SAR of a series of potent A2aR/A2bR antagonists culminating in the discovery of etrumadenant.
Targeting the TGF-ß Pathway for Checkpoint Resistance
Innate and therapy-induced resistance to checkpoint inhibitors limit the response rate in many cancers. An increased TGF-ß signature is linked to poor clinical outcomes and checkpoint resistance. avß8 controls localized and cell-type-specific activation of TGF-ß 1 and 3 to negatively regulate immunity and promotes tolerance. Selective avß8 inhibition is a safe and efficient approach to reverse TGF-ß-driven immunosuppression, improving anti-tumor adaptive immune responses and immune infiltration into the TME.
Targeting Integrins for Immuno-Oncology
The av integrins (avb1, avb3, avb5, avb6, avb8) are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. I will discuss the role of integrins in immuno-oncology and will describe the development of our integrin inhibitor library. I will also present the challenges in targeting integrins with small molecule drugs.
Transition to Lunch12:05 pm
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:15 pm
Session Break12:45 pm
INNATE IMMUNITY TARGETS
Identification of a Novel Class of Highly Potent, CNS-Penetrant, NLRP3-Specific Inhibitors
BioAge is analyzing proprietary human-omics and longitudinal health outcome data to identify novel neurodegeneration drug targets. Our analyses showed that NLRP3 levels rise with age and correlate positively with mortality and cognitive decline. We have synthesized new compounds that inhibit NLRP3 inflammasome in vitro and in vivo, are as or more potent than known NLRP3 inhibitors, have novel structures and chemical properties, and penetrate the blood-brain barrier.
Targeting RIG-I for Cancer
I will discuss novel RIG-I agonists which we are initially advancing clinical against influenza, but that also plays a role in cancer due to its central role in innate immunity. Activation of RIG-I induces interferon signaling cascades that activate the immune system to recognize tumor cells.
Targeted Upregulation of STING
Modulating target proteins via the ubiquitin-proteasome system has recently broadened the scope of pharmacological inventions. Stimulator of interferon genes (STING) activation is a promising strategy for immuno-oncology via promoting systemic antitumor immunity. However, from the current clinical investigations of STING agonists, dysregulated STING expression or poor STING agonist pharmacokinetics pose major challenges that limit the robust antitumor response. Herein, we propose UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to overcome these limitations.
Refreshment Break in the Exhibit Hall with Poster Viewing3:20 pm
PLENARY KEYNOTE SESSION
Plenary Keynote Introduction (Sponsorship Opportunity Available)4:35 pm
Targeting Nodes and Edges in Protein Networks
Protein interaction networks consist of protein nodes and interaction edges. We aim to inhibit or stabilize specific protein-protein interactions to dissect these complex networks for chemical biology and therapeutics discovery. Through covalent fragment-based approaches, we discovered compounds that selectively stabilized the chaperone 14-3-3 bound to diverse client proteins and altered their function. Additionally, function-selective inhibitors for the multifunctional enzyme VCP/p97 are providing new tools and drug leads for cancer.
Welcome Reception in the Exhibit Hall with Poster Viewing5:30 pm
Close of Day6:30 pm
Registration Open7:00 am
In-Person Group Discussions with Continental Breakfast7:45 am
What Are Your Small Molecule Lead Generation Challenges?
- TPD strategies and hurdles for cancer & autoimmunity
- Favorite lead generation approach for small molecules: when to use DEL vs. FBDD vs. HTS?
- Pain points
FRAGMENTS AND TARGETED PROTEIN DEGRADATION APPROACHES
FEATURED PRESENTATION: Fragment Approaches for Discovering Tissue-Specific E3 Ligases and β-Catenin Degraders
I will present how we've applied fragment-based methods to discover ligands for tissue-specific E3 ligases. I will also cover our work on discovering bifunctional degraders for β-catenin. This highly sought-after but difficult-to-drug intracellular target is part of a multi-functional cellular signaling complex whose overactivity contributes to the development of specific cancers and other diseases.
Coffee Break in the Exhibit Hall with Poster Awards Announced9:35 am
Poster Award (Sponsorship Opportunity Available)
TPD APPROACHES FOR CANCER
Discovery and Characterization of NVP-DKY709, a First-In-Class Selective IKZF2 Glue Degrader for Immuno-Oncology Applications
IKZF2 (Helios) is a member of the Ikaros family of zinc finger transcription factors. IKZF2 genetic knockout in mice was shown to destabilize immune-repressive regulatory T cells (Tregs) and it was hypothesized that selective IKZF2 downregulation might safely enhance immune responses to tumors. Here, we present the development of NVP-DKY709, a reprogrammed IMiD-derived molecule that selectivity degrades IKZF2/4 but not IKZF1/3. Non-human primates treated with DKY709 display rapid and sustained degradation of IKZF2 in peripheral blood cells and enhanced response to immunization. DKY709 is a first-in-class selective IKZF2/4 degrader being investigated in human clinical trials as an immunomodulatory drug.
A Degrader of BTK and IKZF
I describe preclinical and clinical data for NX2127, a degrader of Bruton Tyrosine Kinase (BTK), a master regulator of B cells and implicated in cancer. We developed two unique and functionally distinct BTK degraders that harness cereblon (CRBN), an E3 ligase active in hematopoietic cells. I describe the BTK degrader that also has the ability to induce degradation of neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3).
Targeting CBP/p300 - Inhibition vs Degradation for Potent Anti-tumor Efficacy
E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are key transcriptional co-activators that play a critical role in gene expression in both tumor and immune cells. Our efforts in understanding the distinct advantages of inhibition vs degradation of CBP/p300 for use in cancer therapy resulting from a combination of synthetic lethality, inhibition of pro-tumorigenic signaling and activation of anti-tumor immune response will be presented
Close of Small Molecule Immuno-Modulators Conference12:00 pm