Targeting oncoproteins with a positive selection assay for protein degraders
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A new positive selection assay could enhance the discovery of compounds that degrade previously undruggable proteins.
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In a proof-of-concept screen, IKZF1 fused to DCK identified a CRBN-independent degrader, Spautin-1, alongside iMiD-like compounds, highlighting the assay's utility for uncovering mechanism-agnostic molecular glues.
“in an elegant proof-of-concept screen, iKZF1 was fused to DcK to identify novel molecular glue degraders.given that iKZF1 is a well-established neo-substrate of iMiD-bound cRBN, the identification of a cRBN-independent degrader, Spautin-1, alongside iMiD-like compounds, highlights the assay's utility for uncovering mechanism-agnostic molecular glues (Koduri et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Koduri et al. 2021
The Results and Discussion report that DCK*-IKZF1 screens identified IMiD-like IKZF1 degraders and Spautin-1, which down-regulated IKZF1 even in cells lacking cereblon. The paper does not establish that Spautin-1 is a molecular glue: it says its direct target is unknown and that its slower effect suggests an indirect mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA positive-selection assay based on the suicide protein deoxycytidine kinase (DCK) enables identification of compounds that trigger selective degradation.
“One powerful approach uses a positive-selection assay based on a suicide protein, deoxycytidine kinase (DcK) (Koduri et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Koduri et al. 2021
In this system, engineered DCK phosphorylates the nucleoside analogue BVDU into a toxic product; fusion of DCK to a target protein allows compounds that degrade the target to simultaneously degrade DCK, preventing BVDU toxicity and enabling cell survival.
“in this system, an engineered DcK phosphorylates the nucleoside analogue Bvdu, converting it into a toxic product that poisons the cell.Fusion of DcK to a target protein allows compounds that degrade the target to simultaneously degrade DcK, preventing Bvdu toxicity and enabling cell survival.”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Koduri et al. 2021
Using a small library of compounds enriched in non-IMiD-like metabolic inhibitors, the authors found that Spautin-1 induces IKZF1 destabilization in a CRBN-independent manner.
“Indeed, using a small library of compounds enriched in (non-IMiD-like) metabolic inhibitors, the authors found that the compound Spautin-1 induces IKZF1 destabilization in a CRBN-independent manner.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
The authors engineered a reporter system that converts protein loss into a positive selection output (resistance).
“In brief, the authors engineered a reporter system that converts protein loss into a positive selection output (resistance).”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
Koduri et al. published a target-driven E3-agnostic positive selection assay (up assay) to identify monovalent degraders of IKZF1.
“Koduri et al. published a target-driven E3-agnostic positive selection assay (''up assay'') to identify monovalent degraders of IKZF1.161”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
This study provided proof of principle that phenotypic up assays based on degradation of the protein of interest can be used to identify glue degraders.
“Overall, this study provided proof of principle of how phenotypic ''up assays'' based on degradation of the protein of interest can be used to identify glue degraders.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
Koduri et al. interrogated around 100 newly synthesized analogs of pomalidomide, including classical IKZF1 degraders and a small library of uncharacterized IMiDs.
“Koduri et al. interrogated around 100 newly synthesized analogs of pomalidomide, including the classical IKZF1 degraders and a small library of uncharacterized IMiDs reported in the literature.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
Chemical screens coupled to co-treatment with BVdU allowed identification of novel IMiD-like MG degraders of IKZF1 via concomitant resistance, e.g. MI-2-61.
“Chemical screens coupled to co-treatment with BVdU allowed them to identify novel IMiD-like MG degraders of IKZF1 via the concomitant resistance (e.g., MI-2-61) (Fig. 7 and 8).”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [161]
Targeted discovery of degrader compounds against oncoproteins in a cell-based system has enabled the discovery of novel cereblon (CRBN)-dependent and CRBN-independent IKAROS family zinc finger 1 (IKZF1) degraders.
“More recently, targeted discovery of degrader compounds against oncoproteins in a cell-based system has enabled the discovery of novel cereblon (CRBN)-dependent and CRBN-independent IKAROS family zinc finger 1 (IKZF1) degraders235, suggesting that screening for degraders against a target of choice is a strategy that can yield a bounty of phenotypically relevant degrader molecules.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [235]
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Distinct Regulation of ASCL1 by the Cell Cycle and Chemotherapy in Small Cell Lung Cancer
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Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs
Winter, G. E. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00191 · Cited by 12 · see citing works
Cereblon target validation using a covalent inhibitor of neosubstrate recruitment
Dann, G. P., Liu, H., Nowak, R. P., & Jones, L. H. (2022) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2022.08.056 · Cited by 11 · see citing works
From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
“…degrader, Spautin-1, alongside iMiD-like compounds, highlights the assay’s utility for uncovering mechanism-agnostic molecular glues (Koduri et al. 2021). this approach has since been adapted to function alongside cRiSPR-cas9 technology, both genome-wide knockout and base-editor…”
Abu‐Remaileh, M., Persky, N. S., Lee, Y., Root, D. E., & Kaelin, W. G. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2410356121 · Cited by 10 · see citing works
Self-citationOpportunities in proximity modulation: Bridging academia and industry
Đikić, I., Mayor‐Ruiz, C., Winter, G. E., Koch, K., Ciulli, A., & Thomä, N. H. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.07.018 · Cited by 9 · see citing works
Molecular Glue Degraders: From Serendipity to Hunting and Design
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Methods to characterize and discover molecular degraders in cells
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Advances in research on potential inhibitors of multiple myeloma
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A Novel Gain-of-Signal Assay to Detect Targeted Protein Degradation
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nuPRISM: Microfluidic Genome-Wide Phenotypic Screening Platform for Cellular Nuclei
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Target agnostic cellular screening in the era of chemically induced proximity
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Self-citationLoss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.
Hong, D.-L., Lyu, Y., Nayak, R., Becker, J., Booker, M. A., Masuzawa, K., Devos, Z., Wang, T.-C., Saito, S., Liu, Q., et al. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.07.023 · Cited by 3 · see citing works
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Optimization and Evaluation of Complementary Degrader Discovery Assays for Application in Screening
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Targeted protein degradation: bridging chemical biology and clinical translation
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Oncogenic Gα signaling requires AP-3-dependent recruitment to the endolysosomal compartment
Shettigar, M., Moulière, S., Isenegger, L., DeVine, A. L., Gstalder, C., Koduri, V., Doench, J. G., Ksander, B. R., Garcia‐Marcos, M., Kaelin, W. G., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2615774123 · Cited by 1 · see citing works
Self-citationPositive selection screen identifies natural product β-catenin inactivators
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Ratiometric transcriptional activation by protein degradation
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Self-citation
- Authors
- Koduri, V., Duplaquet, L., Lampson, B. L., Wang, A. C., Sabet, A. H., Ishoey, M., Paulk, J., Teng, M., Harris, I. S., Endress, J. E., Liu, X., Dasilva, E., Paulo, J. A., Briggs, K. J., Doench, J. G., Ott, C. J., Zhang, T., Donovan, K. A., Fischer, E. S., Gygi, S. P., Gray, N. S., Bradner, J., Medin, J. A., Buhrlage, S. J., Oser, M. G., & Kaelin, W. G.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
- Broad Institute (US)
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
- Medical College of Wisconsin (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Oser, Matthew G.
- Kaelin, William G.
- ORCID
- Koduri, Vidyasagar
- Duplaquet, Leslie
- Lampson, Benjamin L.
- Wang, Adam C.
- Sabet, Amin H.
- Ishoey, Mette
- Paulk, Joshiawa
- Teng, Mingxing
- Harris, Isaac S.
- Endress, Jennifer E.
- Liu, Xiaoxi
- Paulo, Joao A.
- Briggs, Kimberly J.
- Doench, John G.
- Ott, Christopher J.
- Zhang, Tinghu
- Donovan, Katherine A.
- Fischer, Eric S.
- Gygi, Steven P.
- Gray, Nathanael S.
- Bradner, James
- Medin, Jeffrey A.
- Buhrlage, Sara J.
- Oser, Matthew G.
- Kaelin, William G.
- Venue
- Science Advances
- Published
- 2021-02-05
- Volume
- 7
- Issue
- 6
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC7864573
- OpenAlex
- W3126312907
- Cited by
- 44
- References
- 49
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 6 · 2022: 12 · 2021: 3
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R35, T32 NIH Training Grant CA009172, R01 CA214608-03, Pathway to Independence Award R00CA190861)
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA2144608)
- NIGMS (GM132129)
- American Society of Hematology (Research Training Award)
- Carlsbergfondet (Internationalisation Fellowship)
- Damon Runyon Cancer Research Foundation (Clinical Investigator Award)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- protein degraders, undruggable proteins, oncoprotein, immunomodulators, spautin-1, CDK2, ASCL1, CRISPR-Cas9 screen, compound screening, multiple myeloma
- MeSH terms
- Benzylamines, Humans, Quinazolines, Thalidomide, Transcription Factors, Oncogene Proteins, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Basic Helix-Loop-Helix Proteins, Proteolysis, CRISPR-Cas Systems
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