Cambridge Healthtech Instituteの第16回年次会議
2023年4月12 - 13日
Registration Open12:00 pm
Dessert Break in the Exhibit Hall with Poster Viewing12:45 pm
Welcome Remarks1:30 pm
PPI INHIBITOR SUCCESS
MedChem Case Study of HIV Maturation Inhibitor Candidates
GSK3640254 is an HIV-1 maturation inhibitor (MI) with antiviral activity towards a wide range of clinically-relevant polymorphic variants, which has demonstrated efficacy in HIV-1 infected patients in Phase IIb clinical trials. In contrast to classical HIV-1 protease inhibitors that act by binding to the viral protease, GSK3640254 binds to the viral Gal-polyprotein, preventing its final processing by the HIV-1 protease and resulting in the release of an immature, non-infectious virus.
Discovery Chemistry Success: Capsid Assembly Modulators for HBV
Designing small molecule inhibitors and other protein interaction modulators require simple, high-throughput screening methodologies. Lumit Anti-Tag Reagents for Protein Interactions enable in vitro homogenous (no wash) bioluminescent immunoassays to measure protein-protein and protein-small molecule interactions using common protein tags. Here, we demonstrate how Lumit immunoassays can be used to compare binding affinities of PROTACs and molecular glues with their targets and to monitor PROTAC-mediated ternary complex formation.
Refreshment Break in the Exhibit Hall with Poster Viewing3:10 pm
FEATURED PRESENTATION: Inhibitors of the Bcl-2 Family: A Comparative Chemical Analysis
Cancer cells evade programmed cell death through upregulating Bcl-2 proteins, which sequester the apoptosis-inducing BH3 proteins in high-affinity protein-protein interactions. While the therapeutic potential of inhibiting this interaction and inducing cell death has long been recognized, it took several decades to deliver drug candidates with this mode of action. The presentation describes the inherent difficulties of this discovery process and how we and others overcame them.
Small Molecule Inhibitors of TEADs Allosteric Lipid Pocket
The TEAD family of transcription factors are implicated in cancer but developing a central pocket assay posed a hurdle toward fully understanding inhibition. We have overcome the challenges of TEADs central lipid pocket and developed a robust biochemical assay, using structural elucidation and computational chemistry to understand the MOAs for small molecule inhibitors. We provide hypotheses of different MOAs which could contribute to development of more potent and selective inhibitors.
In-Person Group Discussions5:00 pm
Strategies and Best Practices in Targeting PPIs
- Lead generation strategies --which and when? : DEL, FBDD, HTS, VLS, HCS, FA-tethering, etc.
- Covalent irreversible vs reversible modalities
- Differing considerations for PPI inhibitors vs PPI enhancers (glues)
- Best orthogonal biophysical and biochemical approaches: XRC, Cryo-EM, NMR, SPR/GCI, DSF, FRET, MS, FP, and more
- Testing funnels: which techniques to use, and where? (e.g., assessing lead potency vs tracking PPI affinity shifts...)
Close of Day5:45 pm
Registration Open7:15 am
Diversity in Chemistry Breakfast Discussion (Sponsorship Opportunity Available)7:45 am
Diversity in Chemistry beyond Molecules: Gender and More
We encourage all to attend this moderated, audience-interactive discussion session. When it comes to increasing diversity among scientists, there continues to be a drop-off as one moves higher in leadership. Where do systemic challenges remain, what is your experience, and how can we continue to equalize the system?
Topics may include below, but will be guided by audience input:
- Where does the 'drop-off' of women in the chemistry career progression pipeline occur and why?
- How did the pandemic and other sea changes in the past three years bring us closer to or further from equality?
- What issues arose that you thought were solved?
- Diversity in life paths should include us all - how are men and nonbinary scientists being included?
- Intersectionality and equality - what is the experience of women of color, first-generation women scientists, and others?
PLENARY KEYNOTE SESSION
Plenary Keynote Introduction (Sponsorship Opportunity Available)8:35 am
Reflections on a Career as a Medicinal Chemist in Drug Discovery
A successful drug candidate depends on many factors: creativity of scientists involved, effective collaboration and commitment by the team, and the quality of the compound advanced. I reflect on a 40-year career pursuing the discovery of drug candidates designed to address unmet medical need in the cardiovascular, CNS, and viral diseases therapeutic areas and share undervalued strategies and other synthetic chemistry approaches for overcoming specific medicinal chemistry challenges.
Coffee Break in the Exhibit Hall with Poster Viewing9:30 am
DRUGGING DIFFICULT TARGETS
Identification of the in vivo active KRAS G12C Inhibitor BI-0474 via Fragment Based Screening and Optimization of Reversible Binding to KRAS
I describe the discovery of the in vivo active KRASG12C inhibitor BI-0474. We identified small molecules that bind reversibly to the Switch II pocket on KRAS. These binders were optimized by growing toward Cys12 and then attaching the Michael acceptor warhead to react with Cys12. Our approach offers an alternative to discover KRASG12C inhibitors and provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.
Fragment Screening Combined with Corporate Compound Collection Searching: Delivering a Novel Inhibitor of the KEAP1:NRF2 Interaction
A successful fragment screening campaign against KEAP1 provided key starting points and information to generate a highly potent series against this PPI. To develop a second potent series, the key pharmacophoric elements were used to search the GSK collection. An SBDD campaign on the resulting hits generated a second potent series suitable for lead optimisation.
We have used thermophoresis and cryo-EM to determine the modalities of binding of anti-inflammatory drugs, obefazimod and its metabolically modified metabolite ABX464-N-Glu, to the nuclear Cap Binding Complex (CBC) to trigger the specific and selective expression of the anti-inflammatory microRNA miR-124 in vitro and in UC patients. Our results identify a unique interfacial stabilizing mode of action for anti-inflammatory drugs targeting the CBC complex to act selectively on RNA biogenesis.
Targeting Transcription Factor - BAF Interactions in Cancer
Transcription factors (TFs) make for compelling drug targets but have been historically hard to drug. Various TFs work with the BAF remodeling complex to open specific regions of chromatin. Using SPI1 as an example, we will highlight how Foghorn has developed a drug discovery platform to identify and target TF-BAF protein-protein interactions responsible for driving disease.
Drugging an Intracellular PPI Target
Helically constrained (Helicon) peptides are a drug modality that allows the targeting of undruggable protein-protein interactions in cells. We have developed tandem platforms that enable the de novo discovery of helical hits to targets without any prior knowledge of their helix-binding properties, and that enable the rapid optimization of these hits to molecules with drug-like properties via the multiplexed synthesis and screening of thousands of peptides per week.
Transition to Lunch12:40 pm
At X-Chem, we are pushing the limits of DNA-encoded libraries (DEL) to empower our clients’ pursuit of novel small molecules. I will review X-Chem’s innovative approaches for identification of PPI modulators and describe successful applications of DEL in this area. As an experienced service provider, X-Chem offers tools to support successful small molecule hit identification, including screening X-Chem’s diverse set of DELs, target tractability assessments, custom library synthesis, and AI-guided discovery.
Refreshment Break in the Exhibit Hall with Poster Awards Announced1:20 pm
Poster Award (Sponsorship Opportunity Available)
BIOPHYSICAL AND OTHER METHODS FOR PPI-TARGETED DISCOVERY
Utilizing the SPR Chaser Assay in a Medicinal Chemistry Assay Cascade
Selectivity is a key consideration in medicinal chemistry campaigns. When a target has high sequence similarity with off-target proteins, selectivity may be challenging. Where smaller selectivity margins are sufficient, high-quality measurements are key to reliable detection. The long residence time of tight complexes can lead to unfavorably long incubation times in many biochemical/biophysical assays leading to inaccurate measurements. Kinetic measurements (SPR) have the advantage of measuring affinities pre-steady state with high accuracy. The “chaser” SPR method allows accurate measurements of very slow dissociation constants, extending the range of measurable affinities with the high accuracy needed for reliable selectivity margins.
High-Throughput Protein Analysis Enabled by IR-MALDESI-MS
We have adapted and applied IR-MALDESI-MS, a novel label-free tool, for high-throughput (< 1 sample/sec) biochemical and cellular assays. MALDESI-MS allows direct ambient analysis of complex reaction mixtures in common biochemical buffers and cellular media without sample clean-up. Examples of both cellular and biochemical assays will be given along with other potential applications within the lead discovery space.
Leveraging the RAPID Chemoproteomics Platform to Unlock PPI Targets (STING Pathway and More)
RAPID is a next-generation chemoproteomics technology for discovering small molecules that bind to any target of interest inside of a living cell. Using RAPID, we have discovered the first described ligands for the transcription factor IRF3, which drives the interferon response downstream of STING. We will also describe the discovery of an orphan transporter that is required for the uptake of paracrine 2’,3’-cGAMP into primary macrophages.
Networking Refreshment Break3:35 pm
PPI STABILIZERS AND GLUES
Small Molecule Mitofusin Activators and Inhibitors
Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Using structural and biochemical insights, we developed drug screening strategies and identified the first mitofusin activators and inhibitors that directly increase or inhibit mitofusin activity by modulating mitofusin conformations and oligomerization. Characterization of mitofusin modulators in modulating mitochondrial fusion, function, and signaling and their pharmacological potential in diseases will be discussed.
Cereblon Covalent Modulation through Structure-based Design of Histidine-Targeting Chemical Probes
We describe first rational targeting of a specific histidine residue in a protein binding site using sulfonyl exchange chemistry. Using structure-based drug design we incorporated sulfonyl fluoride and triazole reactive group into cereblon binders resulting in potent covalent inhibitors and molecular glues through engagement of His353. Chemical probes and covalent labeling strategy described here will broadly impact this exciting area of therapeutic research.
Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Tauopathies
Normalization of axonal microtubules (MTs) dynamics is a promising strategy to treat neurodegenerative tauopathies, including Alzheimer's disease. Central to this strategy, however, is the identification of MT-stabilizing compounds that could reach effective brain concentrations and doses that would not be systemically toxic. The proposed presentation will provide an overview of structure-activity relationship efforts that led to the identification of selected members of the 1,2,4-triazolo[1,5-a]pyrimidine class as candidates for further development.
Close of Conference5:25 pm