CONFERENCE DAY TWO
Thursday, December 12, 2024
8:00 am Check-In & Morning Coffee
8:40 am Chair’s Opening Remarks
Debunking & Addressing Idiosyncratic Toxicity Amongst Current Covalency Programs to Improve Safety Profiles & Accelerate IND-Filing
9:00 am Profiling Approved Covalent Drugs to Guide Multiparameter Optimization of Covalent Drug Candidates
Synopsis
- Evaluating intrinsic reactivity and in vitro metabolism for representative approved covalent drugs
- Chemoproteomic profiling to gain insights into covalent binding burden and proteome-wide selectivity
- Considerations for optimization of covalent drug candidates based on approved covalent drug profiles
9:30 am Chemoproteomic Profiling of Covalent Inhibitors in Multiple Cell Types to Assess Pharmacological Targets & Off-Target Safety Risks
Synopsis
- Chemoproteomic profiling using clickable probes of covalent inhibitors in multiple cell types is a crucial technique for evaluating their proteome-wide selectivity to assess target engagement and off-targets
- Importance of selecting appropriate cell lines and organ systems for screening covalent inhibitors to comprehensively assess potential off-target toxicities
- While no single method can definitively determine a compound’s propensity for causing DILI, broadening the scope of chemoproteomic profiling to encompass liver systems in the evaluation of covalent inhibitors could pinpoint off-targets to avoid, thereby helping to mitigate the risk of DILI
10:00 am Accelerating “Speed to Answer” for the Discovery of Covalent Therapeutics
Synopsis
- Integrated workflows that utilize standardized plate maps, automated robotics and high-throughput MS instrumentation to maximize the productivity of the already powerful mass spec based technology
- High-throughput MS platform enabling covalent library screening at < 15 seconds per sample enabling collections of >10,000 compounds to be screened in ~ 2 days
- Standardized SOPs using commercially available hardware/software packages producing dozens of potency (Kinact/Ki) and selectivity (peptide mapping) measurements a day
- Activity based protein profiling (ABPP) workflows elucidating both on-target and off[1]target engagement in a cellular setting
Fueling the Covalency Renaissance to Increase Investment & Partnership to Expand the Paradigm of Treatable Diseases
10:15 am Morning Break & Networking
Synopsis
As the research, discovery, and development into covalent therapies continues to progress from strength to strength, it is more important than ever to collaborate and learn with your peers, as we continue to advance these therapies to patients in need. Join your colleagues to share your latest data and have the first look into what your peers are working on!
Igniting Covalent Modalities Beyond Inhibition to Harness Diverse Mechanisms of Action for First-in-Class Covalent Drugs
11:15 am Innovating the Development of Covalent Molecular Glues Displaying Improved Efficacy through Specific & Durable Interactions
Synopsis
- Defining the ligandable space of the Cysteinome
- Utilizing dual-covalent “superglues” to expand the targetable proteome
- What are the consequences of supergluing proteins?
11:45 am Lessons Learned from Developing Covalent Inhibitors & Covalent PROTACs
Synopsis
- Applying chemoproteomics to characterize covalent inhibitor reactivity in the proteome
- Developing a covalent BTK PROTAC with single digit nM DC50
- Elucidating the ternary complex structure of the covalent BTK PROTAC
12:15 pm A Covalent, Allele-Specific Monovalent Degrader for the Treatment of NASH
Synopsis
- Phenotypic screen points to a degrader; MoA determination and target deconvolution
- Chembio and covalency leveraged to identify a clinical candidate
- Carrying and de-risking covalency from discovery to clinical development of asset in FIH
12:45 pm Panel Discussion: Examining Funding & Investor Perspectives to Fulfil the Future Opportunities of Covalent Drug Discovery & Development
Synopsis
- What is investible in the current market?
- What do investors look for when investing in covalent pipelines? Is a particular target or indication of interest?
- How to spark interest from funding and collaboration partners and discussing how assets are considered versus platforms?
- What are the challenges of the covalency modality and bringing these to the clinic?
1:30 pm Lunch Break & Networking
Examining Pre-Clinical & Translational Cases to Inform & De-Risk the Strategy for Progressing Emerging Covalent Compounds Towards a Quicker Approval
2:30 pm Covalent Strategies for Targeting the Kinome
Synopsis
- Describing the synthesis of sulfonyl-triazoles as a new phenol-reactive group for covalent modification of tyrosine and lysine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry
- The reactivity of SuTEx chemistry is highly tunable, which can facilitate optimization of potent and selective binders to orthosteric and allosteric sites on kinases
- Showcasing efforts to use lead SuTEx inhibitors for modulating kinase function in cells
3:00 pm Discovery of the First Approved Covalent FGFR Inhibitor, Futibatinib, by Cysteinomix Drug Discovery Approach
Synopsis
- What is the optimal profile of a covalent drug targeting FGFRs, considering target engagement, PKPD, safety and tolerability?
- How to design covalent binding drugs to capture Cys on highly flexible loop structures
- What is the desirable platform to continuously deliver covalent binding drug candidates into clinical space?
3:30 pm Clinical Development of RSO-021, a Novel Covalent Inhibitor Targeting Mitochondrial PRX3
Synopsis
- What is the optimal profile of a covalent drug targeting PRX3, considering target engagement, PKPD, safety and tolerability?
- How to design and implement clinical trials to validate the safety, efficacy, and specificity of covalent modification strategies and with what biomarkers?
- How to predict and mitigate the long-term effects and potential for cumulative toxicity of covalent drugs in patients?
4:00 pm Chairs Closing Remarks
4:05 pm End of 2nd Covalent Drug Discovery & Development Summit
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