Cambridge Healthtech Institute 第11届
( 蛋白质间交互作用研讨会 )
2018年4月3-4日 | Hilton Bayfront | 加州圣地牙哥
蛋白质间交互作用（PPI）作为药物标的通常是指两个正在交互作用的胞内蛋白质或复杂蛋白质的表面，具有被可侵入细胞的小分子化学物质破坏或稳定的潜力。这点与「传统的」小分子药物标的 ― 酵素蛋白质不同，其活性（或丧失活性）是可透过生物化学分析来测量的。蛋白复合体是许多重要生理学途径的基础，因此而成为治疗化合物的潜在标的。直到最近之前，胞内PPI因其位点通常是平坦且巨大，与小分子药物通常结合的凹沟或袋状位点十分不同，而被认为难以作为标的。此外型态的改变或复合体的破坏，比酵素活性的丧失更不容易侦测。然而随著PPI「热点」特徵的发现，小分子药物所造成的抑制效果也提升了。此外测定蛋白质间交互作用的生物物理学方法也变得更为稳固，更能够应用在药物发现研究上。本研讨会议程将聚集隶属于药厂、大学的药物化学家、生物物理化学家、结构生物学家、发现生物学家，分享其失败及教训，并一同探索这个具有高度潜力成为药物标的的新类别之共通性。
Tuesday, April 3
7:00 am Registration and Morning Coffee
ONCOLOGY PPI TARGETS
8:00 Welcome Remarks
Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute
8:05 Chairperson's Opening Remarks
Laura Silvian, PhD, Principal Scientist and Head, Physical Biochemistry, Biogen
8:10 Enabling Fragment and Structure-Based Discovery for Challenging Targets (Bcl-2, Mcl-1)
Roderick E. Hubbard, PhD, Professor, University of York and Director, Vernalis
Working on unprecedented targets is tough. It can take some time to generate suitable protein, develop an assay that can be trusted, identify tool compounds and design optimised molecules in the absence of structural information. I will describe our approaches to establish fragment and structure-based discovery for such targets, using as examples the early work on Bcl-2 and Mcl-1 with Servier that resulted in compounds that are now in Phase I clinical trials.
8:40 Structure-Based Design of Novel Inhibitors of the MCL-1's Protein-Protein Interaction
Xin Huang, PhD, Principal Scientist, Department of Molecular Engineering, Amgen
Mcl-1, a member of the Bcl-2 family, inhibits pro-death components of the intrinsic apoptosis pathway and thus is a key survival factor in multiple myeloma and other malignancies. Although compelling, targeting disruption of Mcl-1's protein-protein interaction to induce tumor cell death was previously thought to be "un-druggable" due to the high affinities of Mcl-1 to the pro-apoptotic Bcl-2 proteins and lack of a small molecule binding pocket. We report here our structure-based drug design of novel inhibitors of the Mcl-1 that led to AMG 176, a potent, selective, and bioavailable Mcl1 inhibitor in clinical development.
9:10 Presentation to be Announced
Artem Evdokimov, PhD, CSO, HarkerBIO
9:40 Coffee Break
10:05 Discovery of Potent and Selective Mcl-1 Inhibitors Using Fragment Merging and Structure-Guided Design
James (Chris) Tarr, PhD, Drug Discovery Scientist II, Stephen Fesik Laboratory, Department of Biochemistry, Vanderbilt University
Mcl-1 is a member of the Bcl-2 family of proteins responsible for the regulation of apoptosis and a highly validated target for cancer therapy. Using fragment screening by NMR followed by lead optimization employing structure-based design methods, we have developed selective, picomolar inhibitors of Mcl-1. These compounds act via the intrinsic apoptotic pathway, potently inhibit proliferation in cellular assays, and deliver efficacy in xenograft tumor models. Efforts to develop a suitable clinical candidate are underway.
10:35 Targeting Nuclear Lamins to Inhibit DNA Repair
Xiangshu Xiao, PhD, Associate Professor, Physiology and Pharmacology, Oregon Health & Science University
Targeting DNA repair pathways has been validated as a promising strategy to develop novel cancer therapeutics. However, it has been very challenging to target DNA repair proteins. We have discovered a novel role of lamins in DNA repair and have developed the first-in-class small molecules to target lamins to inhibit DNA repair. We will present our exciting discovery in this space.
11:05 Combatting Cancer and Autoimmunity by Targeting Centrosomes and Specific Ubiquitin Ligases
Kamyar Hadian, PhD, Principal Investigator & Head, Assay Development and Screening Platform, Helmholtz Zentrum Muenchen
This lecture will give insights into two studies that deal with the discovery of small molecules that either target centrosomes for cancer therapy or an E2/E3 ligase protein-protein interaction to combat autoimmunity. We were able to validate and characterize these inhibitors in a variety of biochemical as well as cell-based assays. More importantly, we can provide preclinical proof-of-concept in relevant mouse models.
11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:20 pm Session Break
TARGETING VIRAL, NEURODEGENERATION AND OTHER PROTEIN COMPLEXES
1:15 Chairperson's Remarks
Kevin Lumb, PhD, Director, Discovery Sciences, Janssen R&D
1:20 HBV Capsid Assembly Inhibitors
Andrew Cole, PhD, Research Fellow, Medicinal Chemistry, Arbutus
The encapsidation of pregenomic RNA by dimeric units of hepatitis B virus core protein is an essential step in the viral life cycle of HBV, facilitating viral genome relaxed circular DNA synthesis, infectious virion production and maintenance of a nuclear covalently closed circular DNA pool. Small molecules that bind at the core protein dimer:dimer interface have been shown to demonstrate antiviral activity in vitro and in vivo, through interference with the HBV capsid assembly process.
1:50 FEATURED PRESENTATION: Assessing Mitochondrial Quality Control to Inform Discovery of Small Molecules Targeting the Keap1-NRF2 System
Michelangelo Campanella, PhD, PharmD, Professor and Unit Head, Mitochondrial Cell Biology and Pharmacology Research Group RVC and University College London Consortium for Mitochondrial Research
My talk will report upon Nrf2 inducers as pharmacological tolls in mitochondrial quality control operated by targeted autophagy. It will elaborate on the prominent biological activity in cellular homeostasis of the non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitor PMI, which is structurally distinct from the covalent Keap1 modifiers (e.g. sulforaphane) and amenable to therapeutic exploitation. Contextually, a newly devised method for High Throughput Screening (HTS) for this specific category of Keap1-Nrf2 inhibitors will be presented.
2:20 Protein Secretion Inhibitors
Dustin McMinn, PhD, Director, Head of Medicinal Chemistry, Kezar Life Sciences, Inc.
2:50 Drug Leads Originating from the Public/Private Consortium: European Lead Factory
Dimitrios Tzalis, PhD, CEO, Taros Chemicals; Head of Chemistry, European Lead Factory
Highlights of the European Lead Factory (ELF)
- a public-private partnership that provides researchers in Europe a unique platform for translating innovative biology and chemistry into high-quality starting points for drug discovery
- 200.000 de novo synthesized compounds are complimenting 300.000 compounds provided by participating pharmaceutical partners
- So far resulted in >5.000 hit compounds with a defined biological activity from >90 successfully completed HTS and hit evaluation campaigns out of which a significant number of targets are PPIs
3:20 Sponsored Presentation (Opportunity Available)
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Plenary Session Welcome Remarks from Event Director
Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute
4:35 Plenary Keynote Introduction
Kevin Lustig, PhD, CEO, Scientist.com
4:40 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 End of Day
Wednesday, April 4
Day 1 | Day 2
7:30 am Continental Breakfast Breakout Discussions
CANCER, EPIGENETICS AND PPIs
8:30 Chairperson's Remarks
Maurizio Pellecchia, PhD, Professor of Biomedical Sciences, University of California, Riverside (UCR) School of Medicine
8:35 Design of Allosteric K-Ras Inhibitors Targeting the Switch II Pocket
Juan J. Perez, PhD, Professor, Department of Chemical Engineering, Universitat Politecnica de Catalunya, Barcelona
K-Ras is an oncoprotein involved in numerous cancers. Inhibition of K-Ras has been elusive for many years because it cannot be competitive, due to the high affinity of the protein for GTP. Recently, small molecule inhibitors targeting the G12C K-Ras mutant have been disclosed. These molecules produce their action binding irreversibly into the inducible switch II pocket. In the present communication, we describe a novel series of reversible switch II inhibitors with nanomolar affinity.
9:05 NuRD Epigenetic Complex: An Emerging Target for Cancer Chemo-Sensitization
Elmar Nurmemmedov, PhD, MBA, Assistant Professor, Director of Drug Discovery, Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute
NuRD complex plays a major role in the regulation of gene expression, chromatin organization, DNA damage repair, and genomic stability. NuRD complex is also involved in acquired resistance to chemotherapies in a number of cancers, including deadly brain cancers. Targeting RBBP4, an integral component of this complex, sensitizes resistant cancer cells to chemotherapy. We developed an approach that enables inhibition of RBBP4 and leads to selective elimination of resistant cancer cells; this is a new direction in targeting of chemo-resistant cancer cells.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
FRAGMENT-BASED APPROACHES TO FIND PPI INHIBITORS
10:30 Fragment-Based Discovery of a Chemical Probe for the NSD3-PWWP-1 Domain
Jark Bottcher, Principal Scientist, Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG
We describe the fragment-based discovery of molecules binding to the proposed methyl-lysine binding site of the PWWP-1 domain of NSD3. Supported by a virtual screening approach and subsequent structure-based optimization, the initial hits were optimized into a chemical probe with confirmed binding in cellular assays. The probe and the related negative control can be used to explore the functions of the PWWP-1 domain.
11:00 Lead Generation without an X-Ray Crystal Structure: An NMR Method to Probe Protein-Ligand Complexes
Julien Orts, PhD, Professor, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology ETH
My talk is about a NMR method to solve protein-ligand complex structure. I will present two or three examples of this method applied to finding inhibitors against specific PPI targets.
11:30 In silico Fragment Screening to Identify Cryptic Pockets and Allosteric Sites for PPI Inhibitor Development
Ben Cossins, PhD, Principal Scientist, UCB Pharma
Drug development is increasingly difficult and expensive. Valuable targets are not always amenable to modulation by small molecules and resources are often directed towards seemingly intractable targets. We have been building and applying molecular dynamics based fragment screening and de novo design approaches to try and understand ligandability and functionability for protein-protein interaction targets. We believe this approach can steer us towards hit compounds for tractable PPI targets.
12:00 pm End of Conference