Group Winter

Molecular glue degraders: chemical probing and functional characterization of DCAFs

Group Leader

Georg Winter

Georg Winter obtained his PhD from the Medical University of Vienna under the supervision of Giulio Superti-Furga, and went on as a postdoc with James Bradner at the Dana Farber Cancer Institute/Harvard Medical School. Georg was recruited as a CeMM Principal Investigator in 2016 where his research is now focused on using the unique molecular pharmacology of targeted protein degradation.

  • Institute CeMM - Research Center for Molecular Medicine
  • Phone +43 40160 70031
  • Mail gwinter@cemm.oeaw.ac.at
  • Web https://www.winter-lab.com/

Projects within consortium

Our lab is fascinated by research at the interface of chemical biology, gene regulation, proteolysis and cancer. In my research laboratory, we want to develop and apply novel chemical tools to probe and understand biological processes at a high kinetic resolution. In all aspects of our research, we aim to describe and comprehend research questions on a systems-wide level. We are deploying an integrative research strategy to understand how transcriptional networks are rewired in order to sustain an oncogenic state and how we could target resulting dependencies on the transcriptional machinery or associated chromatin regulators. In particular, we are trying to further accelerate the emerging field of targeted protein degradation and leverage its unique molecular pharmacology to elevate our understanding of oncogenic gene regulation and proteostasis.

Here, we propose a multi-disciplinary approach to chemically probe DCAFs to identify novel small molecular glues capable of re-directing their activity. Towards that end, we will deploy a scalable screening system to identify small-molecules capable of binding to DCAFs in cells. This will be followed by a target identification campaign supported by quantitative proteomics and chemical genetics strategies. Finally, we aim to elucidate structural determinants for the drug-induced molecular recognition of neo-substrates by deciphering the underpinning degron sequence and assaying kinetic determinants of ternary complex formation. If successful, this proposal will unlock novel corners of the “undruggable proteome” by identifying novel molecular glues to hijack the activity of DCAFs to degrade proteins outside the scope of traditional ligand-discovery efforts.

Two different strategies to induce targeted protein degradation. (a) Molecular glues are monovalent compounds that induce the dimerization of two proteins, here an E3 ligase substrate receptor and a neo-substrate. (b) PROTACs are heterobifunctional degraders that can individually bind to the E3 ligase and the protein of interest.

Targeted Protein Degradation as a Validation Strategy. Crucial features are compared among the three key perturbation-approaches in a semi-quantitative manner.

Project members

  • Postdoc

    Marko Cigler

    SFB Member

  • Technical Assistant

    Sophie Bauer

    Associated

  • PhD Student

    Alexander Hanzl

    Associated

  • PhD Student

    Amanda Ng

    Associated

Targeted Protein Degradation related publications by Group Winter

  • 2020 Rational discovery of molecular glue degraders via scalable chemical profiling Nature Chemical Biology Mayor-Ruiz C, Bauer S, Brand M, Kozicka Z, Siklos M, Imrichova H, Kaltheuner IH, Hahn E, Seiler K, Koren A, Petzold G, Fellner M, Bock C, Müller AC, Zuber J, Geyer M, Thomä NH, Kubicek S, Winter GE Go to publication →
  • 2020 Selective Mediator dependence of cell-type-specifying transcription Nature Genetics Jaeger MG, Schwalb B, Mackowiak SD, Velychko T, Hanzl A, Imrichova H, Brand M, Agerer B, Chorn S, Nabet B, Ferguson FM, Müller AC, Bergthaler A, Gray NS, Bradner JE, Bock C, Hnisz D, Cramer P, Winter GE Go to publication →
  • 2020 Targeted protein degradation: current and future challenges Curr. Opin. Chem. Biol. Hanzl A. Winter GE Go to publication →
  • 2019 Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation Mol. Cell Mayor-Ruiz C, Jaeger MG, Bauer S, Brand M, Sin C, Hanzl A, Mueller AC, Menche J, Winter GE Go to publication →
  • 2019 MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation Nature Genetics Sdelci S, Rendeiro AF, Rathert P, You W, Lin JG, Ringler A, Hofstätter G, Moll HP, Gürtl B, Farlik M, Schick S, Klepsch F, Oldach M, Buphamalai P, Schischlik F, Májek P, Parapatics K, Schmidl C, Schuster M, Penz T, Buckley DL, Hudecz O, Imre R, Wang SY, Maric HM, Kralovics R, Bennett KL, Müller AC, Mechtler K, Menche J, Bradner JE, Winter GE, Klavins K, Casanova E, Bock C, Zuber J, Kubicek S Go to publication →
  • 2019 Locus-Specific Knock-in of a degradable tag for target validation studies Methods Mol. Biol. Brand M, Winter GE Go to publication →
  • 2019 Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML Cell Chem. Biology Brand M, Jiang B, Bauer S, Donovan KA, Liang Y, Wang ES, Nowak RP, Yuan JC, Zhang T, Kwiatkowski N, Müller AC, Fischer ES, Gray NS, Winter GE Go to publication →
  • 2019 Identification and characterization of cancer vulnerabilities via targeted protein degradation Drug Discov. Today Technol. Mayor-Ruiz C, Winter GE Go to publication →
  • 2018 LZTR1 is a regulator of RAS ubiquitination and signaling Science Bigenzahn JW, Collu GM, Kartnig F, Pieraks M, Vladimer GI, Heinz LX, Sedlyarov V, Schischlik F, Fauster A, Rebsamen M, Parapatics K, Blomen VA, Müller AC, Winter GE, Kralovics R, Brummelkamp TR, Mlodzik M, Superti-Furga G Go to publication →
  • 2018 Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma Proc. Natl. Acad. Sci. USA Xu L, Chen Y, Mayakonda A, Koh L, Chong YK, Buckley DL, Sandanaraj E, Lim SW, Lin RY, Ke XY, Huang ML, Chen J, Sun W, Wang LZ, Goh BC, Dinh HQ, Kappei D, Winter GE, Ding LW, Ang BT, Berman BP, Bradner JE, Tang C, Koeffler HP Go to publication →
  • 2018 The dTAG system for immediate and target-specific protein degradation Nat. Chem. Biol. Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, Leggett AL, Erb MA, Lawlor MA, Souza A, Scott TG, Vittori S, Perry JA, Qi J, Winter GE, Wong KK, Gray NS, Bradner JE Go to publication →
  • 2018 Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands Nat. Chem. Biol. Gechijian LN, Buckley DL, Lawlor MA, Reyes JM, Paulk J, Ott CJ, Winter GE, Erb MA, Scott TG, Xu M, Seo HS, Dhe-Paganon S, Kwiatkowski NP, Perry JA, Qi J, Gray NS, Bradner JE Go to publication →
  • 2018 Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders ACS Chem. Biol. Ishoey M, Chorn S, Singh N, Jaeger MG, Brand M, Paulk J, Bauer S, Erb MA, Parapatics K, Müller AC, Bennett KL, Ecker GF, Bradner JE, Winter GE Go to publication →
  • 2018 Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules Front. Immunol. Moser SC, Voerman JSA, Buckley DL, Winter GE, Schliehe C Go to publication →
  • 2018 Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation Nat. Chem. Biol. Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, Zhang T, Kwiatkowski N, Boukhali M, Green JL, Haas W, Nomanbhoy T, Fischer ES, Young RA, Bradner JE, Winter GE, Gray NS Go to publication →
  • 2017 MELK is not necessary for the proliferation of basal-like breast cancer cells eLife Huang HT, Seo HS, Zhang T, Wang Y, Jiang B, Li Q, Buckley DL, Nabet B, Roberts JM, Paulk J, Dastjerdi S, Winter GE, McLauchlan H, Moran J, Bradner JE, Eck MJ, Dhe-Paganon S, Zhao JJ, Gray NS Go to publication →
  • 2017 BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment Mol. Cell Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE Go to publication →
  • 2017 Transcription control by the ENL YEATS domain in acute leukaemia Nature Erb MA, Scott TG, Li BE, Xie H, Paulk J, Seo HS, Souza A, Roberts JM, Dastjerdi S, Buckley DL, Sanjana NE, Shalem O, Nabet B, Zeid R, Offei-Addo NK, Dhe-Paganon S, Zhang F, Orkin SH, Winter GE, Bradner JE Go to publication →
  • 2015 DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation Science Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE Go to publication →