Cambridge Healthtech Institute’s 15^th Annual Mastering Medicinal Chemistry conference will bring together senior level medicinal chemists in pharmaceutical, biotech, and academia. Through new case studies, informative panel discussions, high-level poster presentations, and interactive breakout discussions, top scientists will share new insights into small molecules. This event will cover key topics currently facing medicinal chemists, including emerging targets, receptor kinetics and high-throughput experimentation. The Mastering Medicinal Chemistry conference- Part 1 will focus on the recent medicinal chemistry advancements in the field of immuno-oncology.

Final Agenda

Tuesday, June 19

7:30 am Registration Open (America Foyer) and Morning Coffee (Foyer)

TARGETING THE CANCER ENVIRONMENT
Gloucester (2nd Floor)

8:15 Chairperson’s Opening Remarks

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

8:20 Challenges in Phenotypic, Target Agnostic Drug Discovery: Lessons Learned from a Cell-Based Screen Designed to Identify Small Molecules that Decrease C-MYC in Cancer Cells

Jesus Medina, PhD, Manager, Medicinal Chemistry, GlaxoSmithKline

One of the key challenges in cell-based phenotypic drug discovery efforts is the early assessment of the validity and viability of hits obtained from the screen. Using our c-MYC cellular screen as an example, we describe a strategy to determine whether the MOA of the hits has in vivo translatability. The details of our screening strategy/triage campaign, molecular target identification efforts, results from in vivo studies, and the lessons learned along the way will be discussed.

8:50 Rational Design of AKR1C3 Inhibitors as Chemotherapeutic Potentiators

Paul Trippier, PhD, Professor, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center

Aldo–keto reductase 1C3 (AKR1C3) catalyzes the downstream conversion of androgen precursors to the potent androgen receptor ligands testosterone and 5α-dihydrotestosterone, and conversion of PGD2 to 11β-PGF2α and PGF2α prostanoids and hence acts as an important regulator of myeloid cell proliferation and differentiation. The enzyme is highly upregulated in prostate cancer and a number of leukemias. We have designed potent and highly selective inhibitors that act to potentiate clinical chemotherapeutics >200-fold. Such action results in reduced dosing, reduced toxic side effects and completely counters AKR1C3-mediated drug resistance. Our inhibitors provide a strategy for treating vulnerable patients diagnosed with these and other neoplasms in combination with existing chemotherapeutics

9:20 Discovery and Preclinical Characterization of GSK532, a Highly Efficacious STING Agonist for Immuno-Oncology

Yiqian Lian, PhD, Program Team Leader, Immuno-Oncology & Combinations DPU, GlaxoSmithKline

The cGAS-STING pathway plays a crucial role in body’s spontaneous sensing of tumor by the immune system. Unlike checkpoint inhibitors that unleash the body's tumor immune response, STING agonists prime tumor immunity by initiating tumor antigen presentation and tumor specific T-cell response. Herein, we report the discovery of highly efficacious novel STING agonist GSK532 for application in immuno-oncology.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

SMALL MOLECULES FOR IMMUNONCOLOGY
Gloucester (2nd Floor)

10:35 Selective Inhibitors of CLK And DYRK Kinases and Their Anticancer Activity

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

CDC2-like kinase (CLK) and dual specific tyrosine phosphorylation-regulated kinase (DYRK) control the mRNA splicing events via priming phosphorylation of key SF members of the spliceosome. CLK and DYRK are aberrantly activated in a number of cancers and are attractive targets for developing anticancer therapy. We describe our SAR results of a class of novel water-soluble benzimidazoles as selective CLK/DYRK inhibitors. In vitro activity in the NCI60 panel screen of the advanced lead candidates, as well as in vivo efficacy in established prostate cancer tumor models, will be presented.

11:05 Modulation of Innate B1 Lymphocyte Immune Response in Cancer

Nikolai Tupitsyn, PhD, Professor, Cancer Immunology, Lab, Blokhin Cancer Research Center

B1 natural pentameric immunoglobulins can destroy cancer cells. This is selective process usually being directed against tumor associated glycans not expressed by normal cells. Monoclonal antibodies to tumor associated glycan proved their efficacy in gastric cancer. Is there any possibility to use immunoadjuvants to elevate natural B1 immunity to effective level?

11:35 Sponsored Presentation (Opportunity Available)

12:05 pm Session Break

12:10 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:40 Session Break

KINASE INHIBITORS FOR CANCER
Gloucester (2nd Floor)

1:15 Chairperson’s Remarks

Atli Thorarensen, PhD, Research Fellow, BioTc Medicinal Chemistry, Pfizer

1:20 Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors

Neil Grimster, Senior Scientist, Oncology Chemistry, AstraZeneca

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling, and have thus been implicated in both cancer and inflammatory diseases. The development of small molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Here we present the discovery of a potent and orally bioavailable JAK1 inhibitor, which possess ~1000 fold selectivity over the other highly homologous JAK family members, and good selectivity over kinases in general.

1:50 Optimization of Kinact Delivers a First in Class Specific Covalent JAK3 inhibitor PF-06651600

Atli Thorarensen, PhD, Research Fellow, BioTc Medicinal Chemistry, Pfizer

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling, and have thus been implicated in both cancer and inflammatory diseases. The development of small molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Here we present the discovery of a potent and orally bioavailable JAK1 inhibitor, which possess ~1000 fold selectivity over the other highly homologous JAK family members, and good selectivity over kinases in general.

2:20 Aspartyl(Asparaginyl)-Beta-Hydroxylase Inhibitors for the Treatment of Cancer

Mark Olsen, PhD, Associate Professor, Medicinal Chemistry, Pharmaceutical Sciences, Arizona College of Pharmacy

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:30 A Kinase Inhibitor for a Chronic Indication: A Case Study in Balancing Selectivity and Safety to Advance Potent, Selective and Orally Bioavailable MAP4K4 Leads to Preclinical Toxicity Studies

Samit Bhattacharya, PhD, Senior Principal Scientist, World Wide Medicinal Chemistry, Pfizer

This presentation will describe the identification of an aminopyridine lead series from virtual screening and evolution of multiple aminopyridine leads that led to discovery of advanced potent, selective and orally bioavailable MAP4K4 inhibitors. Given the concerns of chronic safety for a kinase inhibitor in a non-oncology indication, this presentation will discuss strategies that were employed to advance two chemotypes (PF-06279789 and PF-06745013) with excellent kinase selectivity but orthogonal profiles to assess safety of the mechanism.

IDENTIFICATION OF NOVEL INHIBITORS
Gloucester (2nd Floor)

4:00 Chemogenomic-driven Hit Identification to Deliver Novel dF508 CFTR Corrector Leads

John Mathias, PhD, Senior Director, Head of Inflammation & Immunology Design, Pfizer

4:30 Identification of Low Clearance Indole Acid AMPK Activators for the Treatment of Diabetic Nephropathy

David Ebner, PhD, Senior Scientist, Pfizer Research Labs

5:00 Find Your Table and Meet Your Moderator

5:05 Interactive Breakout Discussion Groups

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.

Developing Anticancer Therapies with Dual Specific Kinases

Lijun Sun, PhD, Director, Center for Drug Discovery and Translational Research,

Beth Israel Deaconess Medical Center, Harvard Medical School

• Dual specific kinases and their benefits in treating cancers
• Other therapeutic areas of interest?
• Potential uses of the DYRK

Safety Considerations of Kinase Inhibitors

Samit Bhattacharya, PhD, Senior Principal Scientist, World Wide Medicinal

• Chronic safety concerns for kinase inhibitors for you in non-oncology indications
• Advancing chemotypes
• Using orthogonal profiles to assess safety

5:45 Reception in the Exhibit Hall with Poster Viewing (America Ballroom)

7:00 Close of Day

Wednesday, June 20

7:45 am Registration Open (America Foyer) and Morning Coffee (Foyer)

IMPROVING KINETICS & PROFILING
Gloucester (2nd Floor)

8:25 Chairperson’s Remarks

Jesus Medina, PhD, Manager, Medicinal Chemistry, GlaxoSmithKline

8:30 Kinetic and Thermodynamic Profiling in Drug Discovery: A Case Study with EED Hit-to-Lead Program

Ying Wang, PhD, Principal Scientist, Department of Chemistry & Technology, AbbVie

Our analysis revealed for the first time that ITC data should be interpreted in the context of chiral purity of the compounds. The thermodynamic signatures of the EED amino pyrrolidine compounds were found to be mainly enthalpy driven with improved enthalpic contributions as the program progressed. We will also present our perspectives on where we are at on harnessing the power of thermodynamic and kinetic profiling in drug discovery.

RORC2 Inverse Agonists: Finding Lipophilic efficiency in a Hydrophobic Pocket

Mark Schnute, PhD, Associate Research Fellow, Medicine Design, Pfizer R&D

Small molecule, inverse agonists of the nuclear hormone receptor RORC2 are potential therapies for several autoimmune diseases through their ability to inhibit pro-inflammatory cytokine production. This presentation will describe how we have used the key design strategies of lipophilic efficiency optimization and understanding the interplay of structure, pharmacology and target residence time to advance a high-throughput screening hit into a highly potent, selective and orally bioavailable compound.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:45 PANEL DISCUSSION: Medicinal Chemistry in the Field on Oncology and Immuno-Oncology

Jesus Medina, PhD, Manager, Medicinal Chemistry, GlaxoSmithKline

Panelists:

Jesus Medina, PhD, Manager, Medicinal Chemistry, GlaxoSmithKline

Atli Thorarensen, PhD, Research Fellow, BioTc Medicinal Chemistry, Pfizer

Samit Bhattacharya, PhD, Senior Principal Scientist, World Wide Medicinal Chemistry, Pfizer

11:45 Session Break

11:50 Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:20 pm Dessert and Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

1:00 PLENARY KEYNOTE SESSION
Essex South

Partnering for Sustainable Funding

The panel is designed to discuss partnering between various stake holders such as drug discovery startups, VC firms, large pharmaceutical companies and academic labs in order to advance new target discovery and preclinical research. VC companies, and pharma search & evaluation departments will be represented on the panel.

Jens Eckstein, PhD, President, SR One

Barbara K. Sosnowski, PhD, Vice President and Global Head, External R&D Innovation, Pharmatherapeutics and WRD External Partnerships, Pfizer, Inc.

Kevin Bitterman, PhD, Partner, Atlas Venture

Vivian Berlin, PhD, Director of Business Development, Life Sciences, Office of Technology Development, Harvard University

Ben Thorner, Senior Vice President and Head, MRL Business Development & Licensing, Merck

Plenary Technology Panel

Advancing Innovation in Drug Discovery and Translational Research

This year’s Plenary Technology Panel features a group of technical experts from life science technology and service companies, who share their perspectives on various trends and tools that will likely change the way in which we traditionally approach preclinical drug discovery and development. Attendees will have an opportunity to ask questions and understand the impact of recent technical advances.

Moderator: Leigh Zawel, PhD, Managing Director, MPM Capital

Ashley Rae Kark, MBS, Director, Corporate Relations, Scientist.com

Stefan Braam, PhD, Technical Director, Ncardia

Mark Paris, PhD, Director, Translational Applications, Mitra Biotech

Edgard Wood, PhD, Senior Research Director, Discovery, Charles River

2:30 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:10 Close of Conference