The ability to chemically disrupt or modify the protein-protein interactions of epigenetic complexes and components of the Ubiquitin Proteasome System (UPS) has recently given rise to a new generation of small molecules with desirable drug-like properties and ability to modulate gene expression and protein homeostasis. Modulation of such cellular machinery can lead to remarkable phenotypic response, and therefore small molecular modulators of these processes are highly sought after. Of particular interest are bromodomain-containing proteins, ubiquitin ligases, histone methyltransferase complexes, as well as the utilization of bivalent inhibitors and targeted protein degradation.

Cambridge Healthtech Institute’s Inaugural Protein-Protein Interactions, Part 2 conference is designed to convene leading academic and industry discovery scientists to share emerging approaches, novel tools, and the discovery of new PPI inhibitors targeting gene expression and protein homeostasis.

Final Agenda

Tuesday, April 25

12:30 pm Registration

NEXT-GENERATION BET BROMODOMAIN INHIBITORS

1:30 Chairperson’s Remarks

Huawei (Ray) Chen, Ph.D., Principal Scientist II, Oncology iMed, AstraZeneca

1:40Design and Optimization of Novel Benzopiperazines as Potent Inhibitors of BET Bromodomains

Dave Millan, Ph.D., Senior Director and Head, Medicinal Chemistry, FORMA Therapeutics

A protein structure-guided drug design approach was employed to explore small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the potency driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving potency alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Lead compounds from the series displayed potent biochemical and cellular activity which translated into excellent in vivo activity in the benchmark cell line MV-4-11.

2:10 Development of Dual‐Activity Small Molecules that Target BRD4 and Dopamine Receptor D2

Jeffrey W. Strovel, Ph.D., President and CEO, ConverGene

Our compounds showed high activity in a binding test against BRD4, exhibited long half-lives and 100% bioavailability upon oral administration, profoundly suppressed MYC expression both in vitro and in vivo, and strongly inhibited growth of AML cells in a mouse xenograft model. Importantly, a lead candidate has been developed from a subclass of our BET inhibitors that showed additional activity against dopamine receptor D2 (DRD2). In addition to being a therapeutic target for psychiatric diseases, DRD2 is emerging as a therapeutic target for cancer/leukemia stem cells.

2:40 Selective BET-BD1 Inhibition Results in Strong Anti-Inflammatory Activity in Animal Models of Autoimmune Disease

Thomas Franch, Ph.D., CSO, Nuevolution AS

Inhibition of BET proteins is relevant for both oncology and inflammatory diseases. As most BET inhibitors reported in the literature are pan-BET inhibitors, the contribution of individual BDs to the biological activity of BET proteins is currently unclear, and domain-specific inhibition (intra- and/or inter-BET) remains largely unexplored. NUE7770 has high potency and pronounced selectivity towards the first BD (BD1) of the BET family. We will present the results of in vivo efficacy studies conducted with NUE7770 in several mouse models of inflammatory and autoimmune disease.

3:10 Selected Poster Presentation: Discovery of Novel Chemistry-Based Approach for 19F NMR Fragment Screening Against BRD4

Tatiana Matviyuk, Ph.D., Principal Scientist, Medicinal Chemistry & CADD, ENAMINE Ltd.

 

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Fragment-Based, Structure-Enabled Approach to the Discovery of Novel Inhibitors of the BET Family of Proteins: ABBV-075 and Others

Le Wang, Ph.D., Principal Research Scientist, Oncology Discovery, Chemistry, AbbVie

Phenotypic cell-based screening assays combined with affinity chromatography and mass-spectrometry identified the BET family of bromodomains as a potential target for blocking proliferation in a variety of cancer cell lines. A 2-dimensional NMR fragment screen was conducted in order to search for novel scaffolds. Protein X-ray co-crystal structures of five NMR fragment screen hits were solved. This is a successful medicinal chemistry story starting from a weak NMR screen fragment to ABBV-075, our clinical candidate.

5:00 A Platform for Development of Combinatorial Inhibitory Chemotypes: A Potent Inhibitor of PI3K, BRD4 and CDK4/6 (SRX-3177) in One Small Molecule

Donald Durden, M.D., Professor, Department of Pediatrics, University of California, San Diego

A novel thienopyranone molecular scaffold has been discovered and modeled in silico to develop chemotypes which selectively inhibit PI3 kinase, the bromodomain protein BRD4 and CDK4/6. Molecular modeling studies and a robust PI-3K, CDK6 and BRD4 BD1 homology model have been developed and will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions.

5:30 Breakout Discussions

6:15 Close of Day

6:30 Dinner Short Courses*

*Separate registration required

Wednesday, April 26

7:45am Plenary Breakfast Presentation: NMR in Fragment-Based Lead Discovery (FBLD)

Stefan Jehle, Ph.D., Product Manager, Bruker BioSpin

NMR is ideally suited for detecting low affinity fragments in solution for FBLD and allows quality control of the screening library on the fly. The large dynamic range with respect to the MW of the target and binding affinities enables its application to a broad range of targets. During this presentation, we will show straight forward NMR methods in FBLD for non-experts, basic principles, data acquisition, data analysis, automation options, software solutions and assay development.

8:30 PLENARY KEYNOTE PRESENTATION

Drug Discovery and Pan-Assay Interference Compounds (PAINS)

Jonathan B. Baell, Ph.D., Professor, Medicinal Chemistry, Monash University

I will discuss issues around the PAINS filter that we published in 2010 and since then has generated much discussion in the industry. The PAINS filter helped explain the difficulties with certain compounds that many hit-to-lead medicinal chemists around the world, principally in academia and small biotechs but to some extent in big pharma also, were encountering. However, because some known drugs contain PAINS, there is the fear that such filters may be too stringent.

9:30 Coffee Break in the Exhibit Hall with Poster Viewing

HISTONE METHYLTRANSFERASE COMPLEX INHIBITORS

10:40 Chairperson’s Remarks

Matthieu Schapira, Ph.D., Principal Investigator, Computational Chemistry, Structural Genomics Consortium, University of Toronto

10:45 Targeting WD40-Repeat Containing Proteins

Matthieu Schapira, Ph.D., Principal Investigator, Computational Chemistry, Structural Genomics Consortium, University of Toronto

WD40-repeat containing proteins exist as part of various protein complexes. There are more than 340 predicted WD40-repeat containing proteins encoded in the human genome. Examples of such proteins are WDR5 and EED which are part of MLL1/SET1 family and PRC2 complexes, respectively. Disrupting the proper interaction of these subunits with catalytic domain of the protein often affect their activity and have been shown to be a reliable approach in discovery of potent, selective and cell active inhibitors for these complexes.

11:15 NMR Guided Discovery of Novel Pharmacological Tools and Therapeutics Targeting PPIs

Maurizio Pellecchia, Ph.D., Professor, Biomedical Sciences; Director Center for Molecular and Translational Medicine, Daniel Hays Endowed Chair in Cancer Research, School of Medicine, University of California Riverside, Riverside

We have recently proposed a novel approach, HTS by NMR, in which the principles of positional scanning combinatorial chemistry and iterative optimizations are combined with protein-NMR spectroscopy to iteratively identify and optimize PPIs antagonists from collections of >100,000 compounds. I will describe recent advances of the proposed method with examples of its application that led to the identification of several pharmacological tools/leads in the area of cancer and neurodegeneration.

11:45Selected Poster Presentation: Smyd2 Vs Smyd3: Structure Based Analysis of Small Molecule Binding Selectivity

Nithya Baburajendran, Ph.D., Postdoctoral Research Fellow, Experimental Therapeutics Center, A*STAR

12:00 pm FEATURED PRESENTATION: Targeting the PRC2 Complex through a Novel Protein-Protein Interaction Inhibitor of EED

Chaohong Sun, Ph.D., Senior Principal Research Scientist; Head, Fragment Based Drug Discovery, and Global Protein Sciences-Small Molecule, AbbVie

In this talk, we will present our discovery of A-395, a first-in-class antagonist of PRC2 protein-protein interactions (PPI). A-395 binds potently to EED, thereby allosterically inhibiting activity of PRC2 complex. It showed potent cellular activity and comparable in vivo activities to known EZH2 enzymatic inhibitors and furthermore, retained potent activity against cell lines resistant to the catalytic inhibitors, suggesting potential clinical benefits of this novel mechanism of targeting PRC2 complex.

12:30 Enjoy Lunch on Your Own

 

1:30 Dessert Break in the Exhibit Hall with Poster Awards

BIVALENT SMALL MOLECULES

2:15 Chairperson’s Remarks

Dave Millan, Ph.D., Senior Director and Head, Medicinal Chemistry, FORMA Therapeutics

2:20 Targeted Protein Degradation by Small Molecules

Kwok-Ho Chan, Ph.D., Marie Skłodowska-Curie Fellow, Ciulli Group, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee

The application of small molecules to induce selected protein degradation is emerging as a transformative new modality of chemical intervention in drug discovery. We have previously shown that linking a VHL ligand that we had discovered with a pan-BET inhibitor creates highly selective PROTAC molecule MZ1. MZ1 triggers preferential intracellular degradation of Brd4, leaving the homologous BET members untouched, and exhibits greater anti-proliferative activity in leukemia cell lines than pan-BET inhibition.

2:50 Targeting BET Protein Degradation for New Cancer Therapeutics

Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor, Medicine; Professor, Medicine, Pharmacology and Medicinal Chemistry; Director, Center for Therapeutics Innovation, University of Michigan

Recently, a new small-molecule approach has been employed to target degradation of BET proteins through the design of bifunctional, Proteolysis-Targeting Chimera (PROTAC) molecules. Based upon our new classes of highly potent small-molecule BET inhibitors, we have designed and optimized highly potent and efficacious small-molecule degraders of BET proteins. We have performed critical and extensive evaluation of our BET degraders for their therapeutic potential and mechanism of action in models of acute leukemia and solid tumors.

3:20 Clinical Candidate AZD5153 Is a Novel Bivalent Inhibitor of BET Bromodomains

Huawei (Ray) Chen, Ph.D., Principal Scientist II, Oncology iMed, AstraZeneca

Here we describe the discovery and characterization of the bivalent BET probe biBET and AZD5153, an orally bioavailable clinical candidate. The avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical tumor models. Our work illustrates a novel concept in ligand design − simultaneous targeting of two separate domains with a drug-like small molecule − providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

3:50 Refreshment Break

TARGETING E3 LIGASES

4:20 De-Risking E3 Ligases with Novel Strategies and Technologies

Alexander Statsyuk, Ph.D., Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

E3 ligase enzyme mechanisms are still being uncovered, preventing the design of the mechanism-based inhibitors. Second, in contrast to protein kinases and methyl transferases, the assays to screen for inhibitors of E3s are complicated and require E1, E2, E3 enzymes, Ub, ATP and additional reagents to quantify a mixture of the reaction products. In this lecture, we will outline general approaches to design E3 ligase inhibitors. We will also outline our progress toward discovery and design of selective inhibitors of E3 ligases using the novel E3 ligase probe UbFluor that we have developed.

4:50 Novel Spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one Compounds as Potent, Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction

Andreas Gollner, Ph.D., Laboratory Head, Medicinal Chemistry, Boehringer Ingelheim

Novel, chemically stable spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one compounds that are not prone to epimerization as observed for other spiro-oxindole MDM2-p53 inhibitors are presented. Structure-based optimization inspired by natural product architectures led to complex fused ring systems ideally suited to interrupt the MDM2-p53 protein-protein interaction. The compounds are highly selective and show excellent in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for BI-0252.

5:20 A New Strategy to Impair Poly-Ubiquitin Chain Formation by Impeding E2/E3 Protein-Protein Interaction

Jara Brenke, Ph.D., Research Scientist, Assay Development and Screening Platform, HelmholtzZentrum München

During the ubiquitination process, assembly of poly-ubiquitin chains is dependent on the protein-protein interaction of the E2-conjugating enzyme to the E3 ligase. This talk will focus on the identification of a novel small molecule inhibiting an E2/E3 interaction. Proven in biochemical and cell-based assays, we can show that the small molecule prevents binding of the E2 to the E3 enzyme, thereby causing impaired formation of poly-ubiquitin chains and interrupted NF-κB signaling in primary mouse and human cells. Supported by beneficial effects in distinct preclinical autoimmune animal models, we demonstrate a novel first-in-class small molecule, which is capable of modulating the ubiquitination pathway by disrupting the E2/E3 protein-protein interaction.

5:50 Close of Conference

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