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Mastering Medicinal Chemistry Conference - Day 2


 

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THURSDAY, MAY 22, 2014

 

7:30 am Interactive Breakout Discussions 

Breakout discussion groups are interactive, guided discussions hosted by a facilitator or set of co-facilitators to discuss some of the key issues raised during the conference. Delegates will join a table of interest and become an active part of the discussion at hand. 

Table 17: Payload and Linker Chemistry 

Moderator: Patrick Beusker, Ph.D., Director, Antibody-Drug Conjugates, Synthon 

  • Novel payloads: What mechanisms of action would we like to have in addition to the ones of those currently in the clinic? How do we get there?
  • Linkers: Cleavable vs. non-cleavable – what is the optimum linker, if any? How and what can we still optimize?
  • Linker-payloads: What is the best way to attach them to the antibody in terms of site and linkage? Can we increase the loading through sophisticated design?

Table 18: Allosteric Modulators 

Moderator: Craig W. Lindsley, Ph.D., Director, Medicinal Chemistry, Vanderbilt University Medical Center 

  • ‘Molecular Switches’ – synthetic and CYP-mediated
  • Screening Paradigms
  • Expansion beyond GPCRs

Table 19: Beyond Rule of Five 

Moderator: Renato Skerlj, Ph.D., Founder, Drug Discovery Consulting LLC; former Head, Small Molecule Discovery, Genzyme, a sanofi company 

  • The Rule of 5: purpose and evolution
  • Inhibiting protein-protein interactions?
  • Empirical rules for outliers: proteins, macrocycles, and natural products?

Table 20: Residence Time and Receptor Kinetics 

Moderator: Stewart L. Fisher, Ph.D., Principal, SL Fisher Consulting, LLC 

  • Strategies and methods for identifying lead series with slow-binding properties
  • Challenges and approaches to optimizing structure:kinetic relationships
  • Translating in vitro slow binding kinetic profiles to physiological disease models

Table 21: What Value Does Modeling Provide to Medicinal Chemistry? 

Moderator: W. Patrick Walters, Ph.D., Principal Research Fellow, Group Head, Computational Sciences, Vertex Pharmaceuticals, Inc. 

Co-moderator: Anthony Nicholls, Ph.D., CEO & Founder, OpenEye Scientific Software 

  • Companies are increasingly pushing modeling tools into the hands of medicinal chemists. Has this been a worthwhile exercise?
  • What types (if any) of modeling tools are currently useful to the day-to-day work of medicinal chemists?
  • What medicinal chemistry problems might be most helped by the use of computational and modeling tools?

 

 

RECEPTOR KINETICS AND RESIDENCE TIME 

RenatoSkerlj

8:35 Chairperson’s Remarks

Renato Skerlj, Ph.D., Founder, Drug Discovery Consulting LLC; former Head, Small Molecule Discovery, Genzyme, a sanofi company





Peter Tonge8:45 Modulating Drug-Target Residence Time and Assessing Target Vulnerability

Peter J. Tonge, Ph.D., Professor, Chemistry, Institute for Chemical

Biology & Drug Discovery, Stony Brook University

Predicting drug efficacy in humans remains a major barrier to the development of novel chemotherapeutics. We propose that the life-time of the drug-target complex (residence time) is of critical importance for determining in vivo drug activity since drug and target are not at equilibrium in vivo. We are currently exploring the molecular factors that control the life-time of the drug-target complex and are using this information to rationally alter residence time. The translation of residence time effects through biological systems of increasing complexity reveals that drug-target kinetics can provide insight into target vulnerability.

RickRoberts

9:05 CRTh2: Can Residence Time Help?

Rick Roberts, Ph.D., Senior Scientist, Medicinal Chemistry, Almirall

The measurement of ligand binding potency is fundamental to medicinal chemistry, however simple potency data gives no indication of the underlying kinetics of the binding and unbinding processes. Binding events can occur over seconds, minutes, hours or days, and these differences can give rise to both desirable and undesirable consequences. The medicinal chemistry community is now embracing the phenomenon of residence time not only by unraveling the possible consequences of fast and slow kinetics, but by harnessing this extra dimension of ligand-target binding. This talk outlines some of the results of our efforts to develop potent, orally bioavailable CRTh2 antagonists with long receptor residence time to prolong the pharmacodynamic effect. Structure Residence Relationships (SRR) revealed the requirement of specific functional groups which bestowed long dissociation half-lives of 24 h and above.

Stewart Fisher

9:25 Translating Slow-Binding Inhibition Kinetics into Cellular and in vivo Effects

Stewart L. Fisher, Ph.D., Principal, SL Fisher Consulting, LLC

This seminar will discuss the concept of target:ligand residence time and the current challenges in translating routine in vivo models. The development of mechanistic pharmacodynamic models that incorporate these features will be presented and demonstrated using data from an antibacterial drug discovery program.

 AnalytiCon Discovery 

9:45 Natural Product-Guided Identification of Novel Sweet Spots in Druggable Space

Christoph_GibsonChristoph Gibson, Ph.D., Director, Medicinal Chemistry, AnalytiCon Discovery

The success rate of medicinal chemistry programs is closely linked to the structural features of the compounds to be optimized. AnalytiCon has built up a unique expertise in introducing favorable natural product motifs into drug discovery programs. Our latest macrocycle series with high scaffold diversity as well as a case study from our autotaxin inhibitor program will be presented illustrating the potential of the chemical space that is accessible to AnalytiCon.

 

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

 

AnnBoriack-Sjodin

10:45 Protein Methyltransferase Inhibitors as Personalized Cancer Therapeutics: DOT1L and EPZ-5676

P. Ann Boriack-Sjodin, Ph.D., Director, Protein and Structural Sciences, Epizyme, Inc.

The enzymatic activity of DOT1L is associated with a chromosomal translocation that is universally found in patients with MLL-rearranged leukemia. Drug discovery efforts have yielded a potent, selective inhibitor of DOT1L (EPZ-5676) that affects the appropriate histone methyl marks in cells and affects tumor growth inhibition in xenograft models.

CASE STUDIES SESSION: PART III 

 

 CollaborativeDrugDiscovery11:05 Modern Drug Research Informatics Applications to CNS, Infectious, Neglected, Rare, and Commercial Diseases 

Barry_BuninBarry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD, Inc)

There are currently hundreds of commodity technologies for handling scientific information – each with its own scope and limitations.  Layering unique collaborative capabilities upon requisite drug discovery database functionality unlocks and amplifies synergy between biologists and chemists.  The application of collaborative technologies to interrogate potency, selectively, and therapeutic windows of small molecule structure activity relationship (SAR) data will be presented in 5 case studies.  Given external (public and collaborative) data grows faster than internal data, novel collaborative technologies to gracefully manage combined external and private data provide an ever-increasing competitive advantage.

  

Vincent Stoll S11:20 BCL Case Study – From Fragment to Clinical Candidate

Vincent S. Stoll, Ph.D., Associate Director, Structural Biology, AbbVie

This presentation will describe the discovery of Bcl drug candidates, from fragments to orally bioavailable drug candidates. The use of high-throughput chemistry and dedicated medicinal chemistry in the optimization of fragment leads into potent molecules with the property optimized features for oral administration will be described. Refinement of understanding of the underlying biology of the Bcl family also leads to changes in requirements for our drug candidates.

Kap Sun Yeung S11:40 Solving hERG Channel Inhibition

Kap-Sun Yeung, Ph.D., Principal Scientist, Discovery Chemistry, Bristol-Myers Squibb

A better understanding of the molecular characteristics of the hERG channel binding pocket and the ambiguous function of a basic amine, optimization of lipophilic ligand efficiency, as well as an appreciation of hERG trafficking inhibition are essential in mitigating the blockade of this cardiac potassium channel during the drug discovery process.

12:00pm Close of Conference

 

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