PROTACs and Beyond
- 단백질분해유도제 컨퍼런스 -
일정 : 2020년 3월 8-9일
개최: 영국, 런던, Hilton London Canary Wharf

신종 코로나바이러스의 영향에 의한 컨퍼런스의 연기·중지 관련
본 컨퍼런스는 신종 코로나바이러스의 확대를 방지하기 위해 연기 또는 중지될 가능성이 있습니다. 컨퍼런스 일정 및 내용의 변경에 관한 최신 정보는 주최사의 웹사이트에서 확인하시거나 메뉴의 문의 페이지를 통해 연락해주시기 바랍니다.
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Cambridge Healthtech Institute(CHI)가 주최하는 PROTACs and Beyond에서는 화학, 생물학, 약리학 등 다양한 분야의 연구자가 한자리에 모여 단백질분해유도제(PROTAC)의 전망 및 표적 단백질 분해를 위한 다양한 전략의 배경 문제에 대해 논의합니다. 이번 컨퍼런스에서는 현재 개발이 진행되고 있는 새로운 분자 분해약 및 링커, 리가아제 등에 관한 세션과 다양한 용도로 사용되며 향후 한층 더 가능성이 확대될 것으로 기대되고 있는 어세이 및 툴에 관한 세션도 예정되어 있습니다.



최종 컨퍼런스 아젠다

3월 8일(일)

유비퀴틴 기반 분해 이후의 전망

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 자연 형태에서 세포 분해 기구의 이용

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 PROTAC용 유비퀴틴 시그널을 분해 이외에 이용하는 방법

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 유비퀴틴 리가아제와 저분자 유발성 표적 제거

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

특별 세션:새로운 리가아제의 탐구

15:35 특별 프레젠테이션 : PROTAC 개발을 위한 툴박스의 확장

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 친화성 지향 단백질 표적화(AdPROM) 시스템에 의한 표적 단백질 분해

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 표적 단백질 분해용 새로운 E3 유비퀴틴 리가아제를 식별하기 위한 표현형 비의존적 방법의 개발

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

3월 9일(월)

분해 연구를 위한 적절한 어세이의 탐구

9:00 Chairperson’s Remarks

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

9:10 새로운 치료법으로서의 표적 단백질 분해 유도

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 암의 어려운 표적용 분해약 개발을 가능하게 하는 대규모 프로테오믹스 접근

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

새로운 분해약의 탐구

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 새로운 치료 모달리티로서의 표적 단백질 분해 유도

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

분해약 설계 및 특이성 향상

13:10 Chairperson’s Remarks

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

13:15 PROTAC 개선을 위한 E3 리가아제의 활성화

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 분해약에 대한 감수성을 높이는 Cullin-RING 리가아제 레퍼토리의 가역성

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

* 주최측 사정에 따라 사전 예고없이 프로그램이 변경될 수 있습니다.






 
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