2016 Archived Content

The Mastering Medicinal Chemistry conference is now in its 14th year and remains a well-established and popular annual event for senior-level medicinal chemists. The 2016 program features the hottest topics in medicinal chemistry from leaders in the pharmaceutical, biotech and academic spaces. Through cutting-edge case studies, panel discussions, poster presentations and breakout discussions, we showcase the biggest opportunities for small molecules. Several topics will be given special coverage, including small molecules in immuno-oncology, covalent inhibitors, receptor kinetics, CNS kinases, macrocycles, screening diversity, high-throughput experimentation, and novel targets such as RNA, and transporters.

Recommended All Access Package:

June 14 SC4: Modern Lead Generation Strategies – Part 1*
June 14 SC7: Modern Lead Generation Strategies – Part 2*
June 15-16: Mastering Medicinal Chemistry 
June 16-17: Property-Based Drug Design in Medicinal Chemistry

* Separate registration required.

Final Agenda

Day 1 | Day 2 | Speaker Biographies | Download Brochure

Wednesday, June 15

7:00 am Registration and Morning Coffee


8:25 Chairperson’s Opening Remarks

Zhonghua Pei, Ph.D., Senior Scientist, Genentech

8:35 Inventing INCB24360 (epacadostat), an Indoleamine-2,3-Dioxygenase-1 (IDO1) Inhibitor for Immuno-Oncology

Andrew P. CombsAndrew P. Combs, Ph.D., Vice President, Medicinal Chemistry, Incyte Corporation

Immunotherapy agents, such as anti-CTLA-4, anti-PD1 and anti-PDL1, have provided unprecedented efficacy in a broad range of tumor types and paved the way for a new paradigm in cancer treatment through inhibition of innate mechanisms subverted by tumors to suppress the immune response. Indoleamine-2,3-dioxygenase-1 (IDO1) emerged as an immunotherapy target due to its role in regulating local T-cell response. In this presentation, we will focus on our data centric medicinal chemistry decision making that culminated in the invention of epacadostat, a first-in-class, potent, selective and orally bioavailable small molecule IDO1 inhibitor. The novel molecular structure provides yet another example of a “rule-of-5 breaking” clinical candidate. Epacadostat in combination with anti-PD1 (pembrolizumab) as a first-line treatment for advanced melanoma is scheduled to enter pivotal phase 3 clinical trials in 2016. Phase 2 clinical trials designed to explore the use of epacadostat in combination with other immunotherapy agents in a variety of tumor types are on-going.

9:05 Developing Novel Synthetic Cyclic Dinucleotide Derivatives which Are Potent Activators of STING

#Chudi Ndubaku, Ph.D., Associate Director, Organic Synthetic Chemistry, Aduro Biotech, Inc.

Stimulator of Interferon Genes (STING) is a key regulator of the innate immune response. It functions by activating a cascade of intracellular signaling events culminating in type-I interferon production. In the tumor microenvironment, this event leads to the priming and activation of antigen-specific, cytotoxic CD8+ T-cells, shown to result in robust anti-tumor activity. STING binds cyclic dinucleotide (CDN) molecules, which are produced by the host cell in response to intracellular DNA sensing. We have identified unnatural CDN molecules that act as potent activators of STING. We will describe the structural basis of CDN binding to STING and efforts to identify improved molecules that will be suitable for clinical utility as immune adjuvants for the treatment of various cancers.

9:35 Discovery and Development of Highly Selective and Orally Bioavailable Macrocyclic IDO-1 Inhibitors

#Tim Briggs, Ph.D., Senior Director, Medicinal Chemistry, Ensemble Therapeutics

Cell active and selective indoleamine-2,3-dioxygenase (IDO) inhibitors were identified from DNA-encoded macrocycle libraries. Rapid advancement has given sub-nM potency on cells and oral bioavailability. Exquisite target selectivity is due to binding to an allosteric region of IDO, rather than the heme or tryptophan-binding region of the active site. The compounds are in development and predicted to enter the clinic in 2017.

10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


10:50 Covalent Inhibitors as an Approach for Challenging Targets

Atli Thorarensen, Ph.D., Research, Fellow, BioTx Medicinal Chemistry, Pfizer

The pharmaceutical industry has in the past decade experienced a declined innovation of small molecular inhibitors gaining FDA approval. There are many suggestive factors contributing to this decline one of which being that therapeutically important targets are increasingly challenging preventing the identification of potent and selective chemical modulators. The backdrop to this as a potential solution is the increased focus on design and development of covalent inhibitors. Covalent inhibitors provide potential solutions to this difficult target space but bring additional challenge in medicinal chemistry design due to inhibitors intrinsic chemical reactivity. This talk will provide an overview of selective covalent drug discovery efforts and what key insights are required for successful covalent drug design.

11:20 Discovery and Optimization of Novel, Covalent Inhibitors of T790M Mutant EGFR

Edward J. Hennessy, Ph.D., Associate Principal Scientist, Oncology iMed, Chemistry, Innovative Medicines and Early Development, AstraZeneca

Covalent kinase inhibitors have garnered significant interest in recent years, and the approval of Tagrisso (AZD9291/osimertinib) for treatment of EGFR T790M non-small cell lung cancer is further evidence of the therapeutic potential of such compounds. In this presentation, we will present a case study on our preclinical discovery efforts towards identifying and optimizing a structurally-differentiated series of covalent inhibitors of this target.

Collaborative Drug Discovery - small logo11:50 CDD Vault: Activity, Registration, Visualization, Collaboration

Anna Coulon Spektor, CDD Customer Success Manager, Support and Training, Collaborative Drug Discovery

CDD Vault is a collaborative platform that is intuitive enough for non-specialists (biologists, chemists, informaticians, project managers) from drug discovery project teams to all embrace. By tapping into business, scientific, and aesthetic drivers across the drug discovery marketplace, the “rising tide lifts all ships”.

AMRI12:05 pm Navigating Today’s Options for External Medicinal Chemistry Research Support

Mark Wolf, Ph.D., Section Head, Medicinal Chemistry, Albany Molecular Research, Inc.

Over the past 20 years, the landscape for outsourcing medicinal chemistry and drug discovery efforts has changed rapidly. This talk will discuss some of the options available to R&D organizations to access external support such as pre-competitive activities, fee-for-service, in-sourcing, outsourcing and collaboration models. The advantages for each approach will be explored.

Hitgen12:20 Luncheon Presentation: Mastering Medicinal Chemistry: Managing the Economics of Serendipity

Barry_MorganBarry Morgan, Ph.D., Visiting Professor, Institute for Molecular Medicine, University of Texas Health Sciences

The challenge of identifying targets that translate into medicines that bring clinical benefit to patients, and the increased cost of R&D in the industry over the past few decades brings focus to the shortcomings of the current model for the development of novel drugs. We will review the issues related to this challenge, and propose that DNA encoded library technology brings disruptive change to the preclinical phase of drug discovery.

12:50 Session Break


1:40 Chairperson’s Remarks

#Timothy P. Heffron, Ph.D., Senior Scientist, Discovery Chemistry, Genentech, Inc.

1:50 The Drug-Target Residence Time Model: An Alternative Approach to Drug Optimization

#Robert A. Copeland, Ph.D., President of Research, CSO, Epizyme, Inc.

Traditional methods view drug-target interactions exclusively in terms of affinity. The drug-target residence time model takes into account dynamics that affect drug binding and dissociation; its key tenet is that the residence time of the drug-target complex and not affinity per se, dictates much of in vivo pharmacology. Here we will introduce this model and highlight key applications.

2:20 The Role of Binding Kinetics in Drug Action

#David Swinney, CEO, iRND3, Institute for Rare and Neglected Diseases

Binding kinetics are integral to a medicine’s molecular mechanism of action (MMOA), and thereby influences efficacy, safety and duration of action. Binding kinetics include equilibrium dissociation constants, association rates and dissociation rates/residence time that can inform chemical optimization. This talk will address the impact of binding kinetics and the equilibrium state of a system on PK/PD relationships.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing


3:35 Kinase Inhibitors for Brain Cancer

#Timothy P. Heffron, Ph.D., Senior Scientist, Discovery Chemistry, Genentech, Inc.

In addition to each of the factors that affect the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancers must also consider the presence of the blood-brain-barrier (BBB). High expression of transporters at the BBB limits most kinase inhibitors from freely reaching CNS malignancies within the brain. This talk will discuss the unmet need for neuro-oncology treatments, the potential of kinase targets in this space and the unique challenges and considerations for brain-penetrant kinase inhibitor programs.

4:05 Discovery of a Potent, Selective and Efficient Inhibitor of IRAK4 from Fragment-Based Drug Design

#Katherine L. Lee, Ph.D., Associate Research Fellow, Worldwide Medicinal Chemistry, Pfizer

IRAK4 is a proximal kinase in the IL-1R and TLR pathways, and an important node in innate immunity. Structure- and property-based optimization of weakly active fragment hits led to a significant increase in IRAK4 potency and the discovery of an exquisitely potent, efficient series of IRAK4 inhibitors with excellent kinome selectivity and good pharmacokinetic properties, culminating in the discovery of a potential first-in-class IRAK4 inhibitor for the treatment of inflammatory disease.

Schrodinger4:35 Integrating Reliable Binding Free Energy Predictions into Drug Discovery

Soumya Ray, Ph.D., Senior Scientist, Drug Discovery Applications Group, Schrödinger

Successful applications of free energy calculations in drug discovery projects are beginning to emerge, as a result of progress in science (improvements to force fields), technology (sufficient conformational sampling via GPUs), and ease-of-use (interfaces and workflows that make FEP accessible to a broader population). Here, we describe the free energy perturbation approach as implemented in FEP+ and highlight the accuracy through extensive retrospective and prospective applications. We demonstrate that the use FEP+ can lead to a measurable and significant acceleration of drug discovery projects in prospective applications.

5:05 Looking at Small Molecules from a Different Angle – Using Bioactivity Data as Compound Descriptors

#Anne Mai Wassermann, Ph.D., Associate Principal Scientist, Cheminformatics, Merck

Traditionally, chemical structures of small molecules have been used as descriptors for hit finding and lead discovery activities, such as library design, hit expansion and target prediction. This talk highlights how biological profiles for small molecules can be used in a complementary fashion to chemical descriptors in drug discovery, enabling the generation of novel hypothesis. Limitations of biological profiles for biologically silent compounds, known as dark chemical matter, will also be discussed.

5:35 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day

Day 1 | Day 2 | Speaker Biographies | Download Brochure

Thursday, June 16

7:00 am Registration.

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants. Details on the topics and moderators are available on the conference website.

Topic: Immuno-Oncology & Small Molecules

Moderator: Zhonghua Pei, Ph.D., Senior Scientist, Genentech

  • What is the advantage and disadvantage of small-molecule IO approach compared to large-molecule approach? e.g. selectivity, safety, dosing regimen, ability to combine  etc. 
  • Are there enough SM targets in the IO field? Is there enough space for companies to work in the crowded SM IO field? What is the winning strategy for the companies that do work in SM IO field? 
  • One of the challenges for IO is to demonstrate pre-clinical efficacy. What is the right strategy? Have we made any progress is this regard? 
  • Is SM IO field similar to the kinase field of ~ 10-15 years ago? Will it ever be as prosperous as the kinase targets?  

Topic: Covalent Inhibitors

Moderator: Atli Thorarensen, Ph.D, Research Fellow, BioTx Medicinal Chemistry, Pfizer

  • Suitability of covalent inhibitors for indications outside oncology
  • Critical assays for optimization of covalent inhibitors
  • What parameters regarding the target would make it an ideal for covalent approach or covalent approaches should be avoided?
  • What additional characterization would you do of a clinical candidate that is a covalent compound compared to a traditional reversible compound?
  • Cysteine trapping is a well-known approach in covalent drug design, how would you approach lysine’s or tyrosine’s?

Topic: Hit Generation

Moderator: - Shirley Louise-May, Advocate, Collaborative Drug Discovery

  • Hit generation approaches - fragment-based methods to chemical biology investigations, natural product derivatives to peptidomimetics and repositioning - how to design for new targets?
  • How to convert these hits to leads - what property optimizations must be considered, by what strategies and with what timings?
  • Recent trends in lead generation ‘tips and tricks from the new-comers and small players; virtual biotechs, expanded informatics providers, university incubators and the like.


8:35 Chairperson’s Remarks

#Paul Richardson, Ph.D., Senior Principal Scientist, Discovery Chemistry, Pfizer

8:45 Improved Efficiency and Scope of Operations with the Use of Flow Chemistry Platforms

Anil Vasudevan, Ph.D., Director, Medicinal Chemistry Technologies, AbbVie, Inc.

Drug Discovery is nowadays considered a race. In this talk, we will describe our efforts to improve efficiency and scope of our medicinal chemistry operations through the use of a variety of flow chemistry based platforms. These include compound library synthesis using segmented flow technology and the access of novel structures through flow based photochemistry and electrochemistry based techniques. Recent efforts in the area of high temperature chemistry will also be presented.

9:15 Discovery and Synthesis of the Macrocyclic EML4-ALK Inhibitor PF-06463922

#Paul Richardson, Ph.D., Senior Principal Scientist, Discovery Chemistry, Pfizer

PF-06463922 is under clinical development as an inhibitor for both wild type ALK and Xalkori resistant ALK mutants. Because brain metastates has been seen in patients with NSCLC, PF-06463922 was also designed to be brain penetrant. Therefore PF-06463922 has the potential to be a best in class ALK inhibitor for the treatment of Xalkori resistant non-small cell lung cancer (NSCLC) patients. The synthesis of PF-06463922 presents a number of challenges, and this presentation will focus on the close interaction between MedChem and Chemical R&D to overcome these challenges, and meet a variety of project timelines. The key step herein is the ring closure to form the final 12-membered macrocycle. The initial approach utilized a conventional macrolactamization approach, and the strategies to expedite this will be discussed. In addition, it was envisioned that novel direct arylation approach could also be utilized to synthesize PF-06463922, and the development, optimization and subsequent scale-up of this route will be presented. This route is three steps shorter, and is expected to provide a higher overall throughput of the desired API.

9:35 Cyclofluidic Integrated Lead Discovery

#Dave Parry, Ph.D., COO, Cyclofluidic

Speeding up the cycle time for the synthesis and assay of new molecules remains of considerable interest and the integration of chemistry with biology enables the rapid determination of biological profiles. Integrated lead discovery, including machine learning algorithms allows early stage projects to move forward rapidly, focussing on the key aspects of evolving SAR relationships and efficient exploration of chemistry space.

9:55 Drug Discovery with Small-Molecule CMRT™ Macrocycles

#Helmut Thomas, Ph.D., DABT, President and CEO, Cyclenium Pharma, Inc.

Macrocycles are increasingly used to exploit difficult disease targets, notably protein-protein interactions, GPCRs, treatment resistant bacteria, viruses and fungi, and CNS-associated targets with limited accessibility related to metabolic and neurodegenerative diseases. CMRT macrocycles have been designed to combine small molecule like properties with attributes compatible with PPI modulation and brain penetration. Their design and use in drug discovery are presented.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing


11:00 Druggable Non-Coding mRNA: Antibacterials Target an RNA Structural Element

#John Howe, Ph.D., Principal Scientist, Infectious Diseases, Merck & Co.

Riboswitches are non-coding RNA structures located in bacterial messenger RNAs that bind endogenous ligands, such as a specific metabolite or ions, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin (RF) riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide (FMN), to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

11:30 Solute Carrier Proteins as a Potential Source of New Drug Targets

David Hepworth, Ph.D., Senior Director, Worldwide Medicinal Chemistry, Pfizer

Solute carriers (SLCs) are biologically important proteins that control movement of small molecules and ions across membranes. Drug classes that target SLCs include SSRIs and SGLT2 inhibitors. While the SLC family appears to be generally small molecule druggable and is similar in size to the Class A GPCRs, the number drug targets is currently around 10x fewer. The presentation will explore this apparent paradox and provide an overview of the current status of SLC drug discovery.

12:00 pm Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing


3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Close of Conference

Day 1 | Day 2 | Speaker Biographies | Download Brochure