The Mastering Medicinal Chemistry conference is now in its fifteenth year and continues to remain one of the most popular events of its kind. Each year, we strive to bring you the hottest topics in medicinal chemistry from leaders in the pharmaceutical, biotech and academic spaces. We showcase the biggest opportunities for small molecules through cutting-edge case studies, panel discussions, poster presentations and breakout discussions. Mastering Medicinal Chemistry – Part 1 will feature emerging targets and the latest breakthroughs in small molecule research for immuno-oncology, autoimmune diseases, neurodegeneration and other CNS disorders, and more.

This conference is followed by Mastering Medicinal Chemistry – Part 2 being held June 14-15, 2017, which will feature case studies and highlights from industry. We cordially invite you to present a poster, or to attend to learn from and network with the leading experts from around the globe.

Final Agenda

Tuesday, June 13

7:00 am Registration Open and Morning Coffee

SMALL MOLECULES IN IMMUNE-ONCOLOGY

8:25 Chairperson’s Opening Remarks

Lijun Sun, Ph.D., Director, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School

8:35 Discovery of PF-06840003, a Novel IDO Inhibitor for Cancer Immunotherapy

Stefano Crosignani, Ph.D., Director, Medicinal Chemistry, iTeos Therapeutics

Tumors use Indoleamine 2-3 dioxygenase to induce an immunosuppressive environment by promoting immune tolerance, effector T-cell anergy and enhanced Treg function. We have identified and characterized a new, highly selective, orally bioavailable IDO-1 inhibitor, PF-0684003. PF-0684003 reverses human T-cell anergy in vitro. It shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties. These studies highlight the strong potential of PF-0684003 as a clinical candidate in immuno-oncology.

9:05 Small Molecule Antagonists of Immune Checkpoint Pathways

Pottayil G. Sasikumar, Ph.D., Associate Research Director, Medicinal Chemistry, Aurigene Discovery Technologies Ltd.

Immune checkpoint antibodies have revolutionized cancer therapy because of their impressive clinical activity. However, they suffer from the shortcomings including the failure to show response in a majority of patients, need to administer by intravenous injection and immune-related adverse events. We are developing small molecule immune checkpoint antagonists that do not exhibit these limitations. CA-170, a candidate from this approach dually targeting PD-L1 and VISTA is now undergoing clinical trials.

9:35 Highly Selective AKR1C3 Inhibitors Significantly Potentiate Antineoplastic Effect of Clinical Chemotherapeutics

Paul Trippier, Ph.D., Assistant Professor, Pharmaceutical Sciences, Texas Tech University Health Sciences Center

AKR1C3 is an enzyme that regulates the production of steroids and prostaglandins implicated in the progression of cancer and plays a role in the metabolism of anticancer agents. Potent and selective AKR1C3 inhibitors act to potentiate the antineoplastic actions of a range of clinically approved chemotherapeutics. Combination treatment of low concentration of AKR1C3 inhibitor and chemotherapeutic provide significant potentiation effect and sensitize resistant cancer cells to the anthracycline drugs.

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

10:50 Novel IDO1 and TDO2 Selective Inhibitors by in silico Screening

Lijun Sun, Ph.D., Director, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School

We conducted in silico screens to identify novel and selective IDO1 and TDO2 inhibitors, respectively. Enzymatic hIDO1 and hTDO2 assays were utilized to confirm inhibitory activity and selectivity. Among the confirmed inhibitors, a series of oxan-4-carboxamides selectively inhibited hIDO1; while a series of substituted 9H-fluorenes were identified as TDO2 selective inhibitors (IC50: 1 µM). In this presentation we will discuss the in silico approach and provide updates on characterization data of the inhibitors.

11:20 PANEL DISCUSSION: Challenges and Opportunities in Developing Small Molecule Based Immune-Oncology Therapies

Moderator:

Stephen Young, Ph.D., Vice President, Business Development, Sygnature Discovery Ltd.

Panelists:

Stefano Crosignani, Ph.D., Director, Medicinal Chemistry, iTeos Therapeutics

Paul Trippier, Ph.D., Assistant Professor, Pharmaceutical Sciences, Texas Tech University Health Sciences Center

Pottayil G. Sasikumar, Ph.D., Associate Research Director, Medicinal Chemistry, Aurigene Discovery Technologies Ltd.

Lijun Sun, Ph.D., Director, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School

11:50 Optimisation of a Series of Potent and Selective Glucocorticoid Receptor Antagonists

Stephen Young, Ph.D., Vice President, Business Development, Sygnature Discovery Ltd.

Glucocorticoids regulate a plethora of biological effects via interaction with the ubiquitously expressed glucocorticoid receptor (GR). Excessive glucocorticoid activity leads to a number of adverse effects, including, glucose intolerance, diabetes and abnormal fat distribution. This presentation will describe the continuing optimisation of a series of 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulphonamides, focusing on efforts to remove off target effects and to maintain a balance of good oral exposure and potent, selective GR antagonism.

12:20 pm Luncheon Presentation: New Strategy to Reduce Hearing Loss Associated with Usher Syndrome

Christopher Lock, B.Sc., Ph.D., Senior Scientist, Discovery, Charles River

Usher syndrome type III, characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 protein (CLRN1). A strategy to identify potential small molecule therapies to mitigate the hearing loss associated with these mutations is demonstrated. This approach can be applied to identify drugs for other protein-destabilizing monogenic disorders. Funded by the Usher III Initiative Research Consortium, the work was carried out by collaborators at Case Western Reserve University, University Hospitals Case Medical Center and Charles River.

12:50 Session Break

NEW TARGETS IN CNS DISEASES, AUTOIMMUNE DISEASES, IMMUNOLOGY AND RARE GENETIC DISEASES

1:40 Chairperson’s Remarks

Paul Trippier, Ph.D., Assistant Professor, Pharmaceutical Sciences, Texas Tech University Health Sciences Center

1:50 Discovery of First in Class, Orally Bioavailable P300/CBP HAT Domain Inhibitors

Michael Michaelides, Ph.D., Head, Oncology Chemistry, Senior Research Fellow, AbbVie

The histone acetyltransferases p300/CBP are key transcriptional co-activators that are essential for a multitude of cellular processes and implicated in human pathological conditions, including cancer. Despite their important epigenetic functions, it has been challenging to develop selective and potent p300/CBP inhibitors. Starting with a screening hit identified via virtual ligand screening we have developed and optimized potent and selective inhibitors that exhibit low plasma clearance and high oral bioavailability.

2:20 Huntington’s Disease: Challenges in Target Validation and Drug Discovery

Celia Dominguez, Ph.D., Vice President, Chemistry, CHDI Management/CHDI Foundation Inc.

CHDI Foundation is a privately funded nonprofit biopharmaceutical research and development organization that is exclusively dedicated to developing therapies for Huntington’s disease (HD), a lethal autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin (HTT) gene. HD patient brains reveal a devastation of the caudate-putamen, and cortico-striatal-thalamo-cortical circuits seem to be particularly affected. Currently, no disease-modifying therapies are available. Herein will present challenges in target validation and drug discovery in the quest to identify potential therapeutics for HD.

2:50 Design and Synthesis of Novel S-Ribosylhomocysteine Analogues

Christiane Chbib, Pharm.D, Ph.D., Assistant Professor, Pharmaceutical Sciences, Larkin College of Pharmacy

New 4-C-Alkyl/aryl-S-ribosylhomocysteine (SRH) analogues and [4-thio]-S-ribosylhomocysteine (SRH) analogues have been designed and synthesized as potential antibacterials. These analogues might impede the S-ribosylhomocysteinase(LuxS)-catalyzed reaction by preventing β-elimination of a homocysteine molecule, and thus depleting the production of quorum sensing signaling molecule AI-2.

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Expanding the Capabilities of Current Biophysical Platforms to Support Preclinical Drug Discovery From Hits-to-Lead Through to Lead Optimization

John G. Quinn, Ph.D., Head of Molecular Biophysics & Senior Scientist, Biochemistry & Cellular Pharmacology, Genentech a member of the Roche Group

Real-time biomolecular interaction analysis accelerates preclinical drug discovery by using increasingly versatile SPR instruments for fragments screens, SAR and MoA. Expanding the capabilities of current SPR platforms by developing unconventional assay formats provided effective solutions where alternative functional assays were either unavailable, or lacked the necessary sensitivity, to measure interaction constants of leads. Elucidating the dependence of cellular efficacy on interaction kinetics supports better data-driven decision making within project teams.

4:35 The Biologist-Med Chemist Interface in Drug Discovery: The Importance of the Assay in Fitting Data to Models to Determine Mechanism of Action

Terry Kenakin, Ph.D., Professor, Department of Pharmacology, University of North Carolina School of Medicine

The muscarinic receptor Gq protein activation profiles of five exemplar molecules (slow binding agonists, partial agonists, inverse agonists, PAM-Agonists and Beta-PAMs) will be compared in calcium and IP1 assays to illustrate how quantitative comparisons to pharmacological models can both identify mechanisms of action and also convert descriptive to predict data for therapeutic systems. The optimal use of these models allow the identification of consistent and simple scales of activity that can guide medicinal chemistry in lead optimization.

5:05 Extended Q&A with Session Speakers

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

6:45 Close of Day

Wednesday, June 14

7:00 am Registration Open

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.

Topic: Current Scope of Pre-Clinical Models of Cancer Immunotherapy

Moderator: Jeffrey Johannes, Ph.D., Associate Principal Scientist, IMED Oncology Medicinal Chemistry, AstraZeneca

• Which in vitro models are used and their advantages and disadvantages?
• Which in vivo models translate best to the clinic?
• How to best mimic the tumor microenvironment?

Topic: Expanding the Range of Druggable Targets

Moderator: Graham Smith, Ph.D., Director, Director Medicinal Chemistry, New Modalities, Medicinal Chemistry, Merck Research Laboratories

• The FDA compendium of drugs addresses less than 10% of the human genome (proteome) families how do we open up new protein classes and their interactions like protein protein interactions and protein RNA/DNA interactions?
• How do we move beyond the human proteome to drugs targeting DNA, RNA, glycosides and lipids?
• What new tools may we need to create to expand our capabilities in these new areas?

Topic: Phenotypic/Pathway Screens and Target De-convolution

Moderator: Celia Dominguez, Ph.D., Vice President, Chemistry, CHDI Management/CHDI Foundation Inc.

• TCell line relevant human disease and the output/readout
• Understand machinery in place/ Secondary and orthogonal assays
• Composition screening collection

DNA-ENCODED LIBRARIES AND NEW CHEMISTRY TECHNOLOGIES

8:35 Chairperson’s Remarks

Graham Smith, Ph.D., Senior Medicinal Chemist, AstraZeneca

8:45 Non-Coding RNA as a Small Molecule Druggable Target

Graham Smith, Ph.D., Senior Medicinal Chemist, AstraZeneca

The human proteome consists of some 25,000 gene targets from which most current drug discovery efforts are based. However, in recent years it has become clear that the human transcriptome contains a similar number of gene targets whose RNA does not code for any protein. The role of these transcribed but non-coding RNA (ncRNA) targets is the subject of much active research. Their genetic linkage to diseases and traits is both numerically and statistically the same as that for the protein coding RNA when using SNPs and GWAS analysis.

9:15 PROTACs: Inducing Protein Degradation as a Therapeutic Strategy

George M. Burslem, Ph.D., Research Associate, Molecular, Cellular and Developmental Biology, Yale University

The Crews lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a technology that overcomes the limitations of the current inhibitor pharmacological paradigm. PROTACs offer a mechanism to irreversibly inhibit protein function by destruction of the target proteins. This approach employs heterobifunctional molecules to recruit target proteins to the cellular quality control machinery, thus leading to their degradation. We have demonstrated the ability to degrade a wide variety of targets.

9:45 Structure-Based Optimization of Non-Natural Peptidic Mcl-1 Inhibitors from a DNA-Encoded Library Screen: Macrocyclization, Binding Kinetics, and Nonlinear SAR

Jeffrey Johannes, Ph.D., Associate Principal Scientist, IMED Oncology Medicinal Chemistry, AstraZeneca

Crystallography showed that a non-natural peptidic DNA-encoded library hit bound to Mcl-1 in a β-turn conformation. Linking of the ends of the peptide to form a macrocycle resulted in an approximately 10-fold improvement in binding potency. Further optimization resulted in a nanomolar Mcl-1 inhibitor that is selective against Bcl-2 and Bcl-xL and able to induce cleaved caspase 3 in MV4-11 cells with an IC50 of 4 µM at 6 hours.

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

11:00 Application of Sulfonyl Fluorides in Drug Discovery

Ariamala Gopalsamy, Ph.D., Associate Research Fellow, Medicine Design, Pfizer, Inc.

Phase II attrition poses a formidable challenge to the pharmaceutical drug development process. There is a need to address this challenge during the pre-clinical discovery phase to build confidence in translation. Chemical probes are highly valuable in this regard during the early discovery phase to identify, validate and assess coverage of molecular targets. Sulfonyl fluorides are proven chemical biology tools and provide a means to interrogate targets even in the absence of reactive cysteine or lysine. Select case studies will be presented to highlight the utility of sulfonyl fluoride probes in the early discovery process.

11:30 Strategic Considerations for the Preparation of Functionalizable Heterocycles

Andrew Flick, Ph.D., Senior Principal Scientist, Global R&D, Pfizer, Inc.

Densely packed arrangements of heteroatoms and stereogenic centers constituting the heterocyclic motifs challenge the limits of current technology, prompting the need for new strategies for the synthesis of these systems. Novel approaches which have demonstrated our access to these challenging molecular architectures will be presented-- a ruthenium-catalyzed hydrogen transfer of 1,3-diols in the presence of alkyl hydrazines to furnish 1,4-disubstituted pyrazoles and a versatile approach to 5,6-fused heteroaromatics will be described which involves the conjugate addition of a metallated 2-fluoropyridine to substituted nitroolefins followed by a tractable 3-step sequence capable of furnishing these highly important bicyclic arrays.

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

1:30 PLENARY KEYNOTE SESSION

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

4:15 Close of Conference