Focus Day

PRE-CONFERENCE FOCUS DAY - SEPTEMBER 21, 2021

8:30 am Registration Opens & Chair’s Opening Remarks

9:00 am A Brief History of Targeted Covalent Drugs: The Journey from Avoided to Essential Medicines

Synopsis

  • Historical impact of covalent drugs and why they were avoided in modern drug discovery
  • The advent of targeted covalent drugs and how they changed the treatment paradigm for lung cancer and leukemia
  • Targeting RAS with covalent inhibitors beyond G12C – covalent PI3K inhibitors and covalent ERK inhibitors and the broader landscape for covalent drugs

9:30 am Covalent Inhibitors of The Malaria Proteasome: New Therapeutics with Overall Reduced Drug Resistance Compared to Reversible Inhibitors

Synopsis

  • The talk will discuss efforts to use selective covalent inhibitors that specifically target the Plasmodium falciparum proteasome as a new anti-malaria strategy
  • Discuss how this class of inhibitors synergizes with existing anti-malarial drugs
  • Demonstrate how covalent inhibitors have the benefit of reduced resistance compared to similar reversible inhibitors

10:00 am CoLDR Chemistry for Targeted Covalent Inhibitors

  • Nir London Senior Scientist & Assistant Professor, The Weizmann Institute of Science

Synopsis

  • Presenting a new electrophile that is suitable for targeted covalent inhibitors
  • Discussing how late-stage incorporation of this electrophile can confer improved properties such as potency and selectivity
  • Installation of suitable cargos as substituents opens the way for small molecule targeted delivery and new protein proximity inducers

10:30 am Live Panel Q&A – Ask Speakers Your Burning Questions

  • Juswinder Singh Founder & Chief Scientific Officer, Ankaa Therapeutics
  • Matthew Bogyo Professor, Stanford University
  • Nir London Senior Scientist & Assistant Professor, The Weizmann Institute of Science
  • Ronen Gabizon Staff Scientist, Weizmann Institute of Science

10:45 am Morning Break & Speed Networking

Synopsis

Reinventing the face-to-face networking in the virtual world. We will pair you up with fellow attendees to break the ice and make new and lasting connections with other experts from industry and academia.

11:45 am PANEL DISCUSSION: Exploring Optimal Targets & Future Landscape of Covalent Inhibition

Synopsis

Covalent inhibitors are becoming increasingly recognized as a critical component in drug discovery and as a potential therapeutic, however for years major challenges continue to exist and cause major setbacks to the field and the question remains as to which target is most optimal to select for covalent modulation. In addition to considering how to select the right target and known off-target effects, this panel will reflect on continual efforts to discover and develop reversible and irreversible covalent drugs, consider the landscape of potential targets, and discuss the remaining limitations this field faces.

12:45 pm Lunch & Networking Break

1:45 pm Computer-Aided Discovery Of an IV-Generation Of EGFR Inhibitors Overcoming C797S Mutation

  • Alessio Lodola Associate Professor of Medicinal Chemistry, Dept. of Food & Drug, University of Parma

Synopsis

  • The emergence of the C797S mutation in EGFR kinase is one the most frequent mechanism of resistance to the III-generation inhibitor osimertinib. The replacement of Cys797 with a less reactive serine prevents the formation of covalent bond between the acrylamide of osimertinib and EGFR making this drug clinically ineffective
  • A feasible option in the search for a IV-generation of EGFR inhibitors is still represented by covalent agents. This approach requires the identification of a suitable nucleophilic residue alternative to Cys797. This residue should be i. proximal to the ATP binding site, ii. accessible to convenient warheads, iii. surrounded by an environment increasing its nucleophilicity, iv. featured by a fundamental biological role so that it would be less prone to mutation than non-essential residues
  • The catalytic lysine of EGFR complies with all these requirements and has thus emerged as a hot spot for covalent drug design. In my talk, I’ll show how molecular simulations can efficiently drive the discovery of novel agents able to overcome C797S mutations

2:15 pm IC50 Determination of Covalent Inhibitors Provides Meaningful Data to Medicinal Chemistry For SAR Optimization Illustrated By The Discovery Of PF-06651600

Synopsis

  • Key consideration for designing assays to measure affinity for covalent inhibitors
  • Why IC50 measurements provides the same information as Kinact/Ki
  • Application of this to the discovery of covalent JAK3 inhibitors in clinical development

2:45 pm Live Panel Q&A – Ask Speakers Your Burning Questions

3:00 pm Afternoon Break & Speed Networking

3:45 pm Covalent Inhibitors for the SARS-Cov-2 Main Protease

  • Wenshe Ray Liu Gradipore Chair and Professor in Chemistry, Texas A&M University

Synopsis

  • By targeting the catalytic cysteine in the SARS-CoV-2 main protease, both reversible and irreversible covalent inhibitors have been developed
  • Some of these inhibitors exhibit a high level of selectivity over human protease and high potency in inhibiting the SARS-CoV-2 infection of mammalian host cells

4:15 pm Reactive Docking: Performing Predictive High-Throughput Virtual Screenings on Proteomes

Synopsis

  • Presenting the Reactive Docking, a structure-based computational method for screening large reactive libraries and predicting the outcome of irreversible binding reactions
  • Outlining how it can identify both residues and ligands most likely to be engaged in covalent modifications without prior knowledge other than the target structure
  • The method is designed to model virtually any warhead and reaction, can be used for early target druggability assessments, and is suitable for very high-throughput virtual screening (HTVS) of potential covalent inhibitors, even on entire proteomes

4:45 pm Live Panel Q&A – Ask Speakers Your Burning Questions

5:00 pm Chair’s Closing Remarks & End of Pre-conference Focus Day