PROTACs and Beyond
開催地:英国、ロンドン、Hilton London Canary Wharf
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Cambridge Healthtech Institute (CHI) 主催のPROTACs and Beyondでは、化学、生物学、薬理学などさまざまな分野の研究者が一堂に会し、タンパク質分解誘導薬 (PROTAC) の展望や標的タンパク質分解のための多様な戦略の背景にある課題について議論します。今度の学会では、現在開発が進められている新たな分子分解薬やリンカー、リガーゼなどに関するセッションに加え、さまざまな用途で使用され、今後さらにその可能性が広がると期待されているアッセイやツールについてのセッションも予定されています。

最終版 学会のアジェンダ



12:50 Organizer’s Welcome Remarks

13:00 Chairperson’s Remarks

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

13:05 自然な形での細胞分解機構の利用

Laura Itzhaki, FRSC, Professor of Structural Pharmacology, Department of Pharmacology, University of Cambridge; CSO, PolyProx Therapeutics

The common underpinning basis of the cell’s proteostasis network is molecular recognition involving the specific interactions of proteins with one another. The Polyproxin™ platform exploits our understanding of these interactions to harness proteostasis networks and thereby manipulate protein stability and disease outcome. The platform comprises libraries of target-engagement modules and degradation-inducing modules in a mix-and-match format to identify the best combination for effective knockdown of the target. The platform can thereby be directed to diverse targets and disease states by co-opting the broadest range of degradation machineries including, but not limited to, the ubiquitin-proteasome system.

13:35 PROTACに対応するユビキチンシグナルを分解以外で利用する方法

Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.

Nature synthesizes multiple poly-ubiquitin chains that extend from seven lysines on the ubiquitin surface. Lys 48 and Lys 63 poly-ubiquitin are primary degradation signals for PROTACs, driven by ubiquitin ligases cereblon, VHL and HDM2. Little is known about the roles of mono-ubiquitin or atypical poly-ubiquitin chains or their cognitive ubiquitin ligases. The roles of classic ubiquitin ligases and atypical ubiquitylation will be discussed with the aim of expanding the horizon of PROTAC drugs beyond protein degradation.

14:05 Cullin-RINGユビキチンリガーゼと低分子誘発性標的除去

Yue Xiong, PhD, William R. Kenan Jr. Professorship of Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen

Development of small molecules to target ubiquitin-dependent degradation of disease-linked proteins represents a promising opportunity for the drug discovery. Multiple such small molecules have been developed based on different E3 ubiquitin ligases. I will discuss the catalytic mechanism, assembly and regulation of cullin-RING E3 ubiquitin ligases (CRLs). I will also present our efforts in developing novel degraders targeting different human cancer protein. Finally, I will share the thoughts on developing novel E3 ligands.

14:35 Exploring New Ligases and Degradation Pathways

Discussion with Session Speakers


15:05 Opening Refreshment Break


15:35 特別プレゼンテーション: PROTAC開発に向けたツールボックスの拡張

Alex Bullock, PhD, Associate Professor, Nuffield Department of Medicine, University of Oxford; Principal Investigator, Structural Genomics Consortium (SGC)

The discovery of PROTACs remains empirical and can fail due to the limited choice of E3s. To date only ~1% of the 600 E3s have been explored for PROTACs. We are developing chemical handles for an expanded set of E3s with distinct structural properties as well as diverse temporal and spatial expression profiles to expand the potential applications of PROTACs for chemical biology and broaden the horizon for future drug discovery efforts.

16:05 親和性指向タンパク質標的化 (AdPROM) システムによる標的タンパク質分解

Gopal Sapkota, PhD, Programme Leader, MRC Protein Phosphorylation & Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee

The AdPROM system utilizes E3 ubiquitin ligases linked to small, polypeptide binders of intracellular proteins of interest (POIs) as protein missiles to target the destruction of the POIs through the proteasome. The system achieves rapid and efficient degradation of target POIs and is versatile. The AdPROM system can not only degrade POIs but also rapidly inform whether different E3 ligases are capable of degrading POIs.

16:35 標的タンパク質分解に対応する新たなE3ユビキチンリガーゼを同定するための表現型非依存的手法の開発

Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

We report a novel, unbiased, phenotypic screening approach for the identification of such chemical matter. The key concept of the assay is the chemical modification of screening compounds and the evaluation of their ability to recruit E3 ligases by a simple fluorescence-based readout in an easy to setup cellular screening system. This combines, for the first time, high-throughput chemistry with high-content screening in living cells.

17:05 TECHNOLOGY PANEL: Advancements in Assays and Technologies for Protein Degradation

Moderator: Markus Queisser, PhD, Scientific Leader, Protein Degradation DPU, R&D Future Pipelines Discovery, GlaxoSmithKline

Panelists: Gary Allenby, PhD, Aurelia Bioscience

Hannah Maple, PhD, Innovation Manager, Bio-Techne

Others to be announced

17:35 Close of Day



9:00 Chairperson’s Remarks

Roy Pollock, PhD, Senior Vice President, Biology, C4 Therapeutics

9:10 新たな治療法としての標的タンパク質分解誘導

Roy Pollock, PhD, Senior Vice President, Biology, C4 Therapeutics

The ability to direct proteins for degradation by the ubiquitin-proteasome system using heterobifunctional small molecules has created a unique opportunity to treat human diseases. Targeted protein degradation (TPD) offers the potential for more profound ablation of protein function and broadens the spectrum of addressable therapeutic targets. In this presentation, I will use BRD4 as a case study to illustrate our approach to TPD including the critical assays used and how they inform on degrader development.

9:40 がんの困難な標的に対応する分解薬開発を可能にする大規模プロテオミクスのアプローチ

Katherine Donovan, PhD, Scientist, Laboratory of Dr. Eric Fischer, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School

Small molecules that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. We and others have demonstrated that efficacious degradation of kinases and other targets can be achieved in vitro and in vivo, however, many targets remain recalcitrant to degradation. In this presentation, I will discuss the use of large-scale chemical-proteomics approaches to accelerate the development of degraders as novel chemical probes for kinases and other disease targets.

10:10 Coffee Break


10:40 Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs

Ronen GabizonRonen Gabizon, PhD, Staff Scientist, Department of Organic Chemistry, Weizmann Institute

Covalent PROTACs are assumed to be inferior due to the non-catalytic nature of their activity. We designed and tested covalent PROTACs targeted against BTK and compared them to non-covalent analogs. We discovered a reversible covalent PROTAC with sub-µM potency and an irreversible covalent PROTAC with nM potency, among the most potent BTK PROTACs reported to date. Our results confirm the potential of covalent PROTACs against proteins that are difficult to target with noncovalent binders. 

11:10 新たな治療モダリティとしての標的タンパク質分解誘導

Nikki Carter, PhD, Associate Director, Discovery Biology, AstraZeneca

This presentation will highlight internal efforts to build state-of-the-art assay cascades towards understanding the molecular mechanism underlying this intriguing biology, the build of a proteomics platform to define the binding and degradation selectivity of protein degraders and the hit finding for novel E3 ligase ligands. The identification of novel degraders against two oncogenic targets and their utility as target validation tools and as potential therapeutics for many solid and haematological malignancies will be described.

11:40 Structure-Based Design of a Macrocyclic PROTAC

Andrea Testa, PhD, Head of Chemistry, Amphista Therapeutics Ltd.

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy that to date remains unprecedented for bifunctional molecules such as PROTAC degraders. The talk will illustrate the design, synthesis, biophysical studies and crystal structure of a macrocyclic PROTAC targeting BET proteins.

12:10 Enjoy Lunch on Your Own

12:40 Session Break


13:10 Chairperson’s Remarks

Nikki Carter, PhD, Associate Director, Discovery Biology, AstraZeneca

13:15 PROTAC改善のためのE3リガーゼの活性化

Jacky Chung, PhD, Scientist, Laboratory of Dr. Sachdev Sidhu, Donnelly Center, University of Toronto

Although the development of PROTACs has garnered significant attention, several challenges remain, including therapeutic dosing. This is largely due to the hook effect resulting from saturating PROTAC molecules. Here, we present our work on finding ways to activate E3 ligases, which should improve the efficiency of a PROTAC. Improving efficiency will decrease the effective dose of a PROTAC and help avoid saturating doses in the clinic.

13:45 分解薬に対する感受性を高めるCullin-RINGリガーゼレパトアの可塑性

Cristina Mayor-Ruiz, Postdoctoral Fellow, Laboratory of Dr. Georg Winter, CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences

We set out to systematically delineate all cellular effectors required for targeted protein degradation (TPD). We found that sensitivity to degraders is mainly dictated by shared modulator networks, with some exciting, ligase-specific differences. Perturbation of these effectors impairs cullin-RING ligase (CRL) plasticity and arrests many of them in a constitutively active state. Collectively, our study informs on regulation of CRLs amenable for TPD, and outlines biomarkers and putative resistance mechanisms for upcoming clinical investigation.

14:15 Mechanistic Modelling of PROTACs

Andreas Hock, PhD, Associate Principal Scientist, Discovery Sciences, AstraZeneca

PROTAC assisted protein degradation is affected by several cellular factors (concentration of target and E3, native turnover rate of target) as well as PROTAC dependent parameters (affinity to target, ligase, ternary complex formation and the rate of ubiquitin transfer). I will present the latest insights into which parameters are critical to understand for the PROTAC mode of action, enable efficacy prediction and how this can be applied to PROTAC optimisation.

14:45 End of Conference/Registration for Short Course

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