Systematic Targeting of Protein Complexes with Molecular COUPLrs
Small molecules that modulate protein complexes have transformed cell biology and oncology, yet few chemical starting points exist to probe protein-protein interactions. To expand this space, we developed molecular COUPLrs, elaborated small molecules flanked by two cysteine‑reactive warheads. Using CONNECT, an integrated chemical proteomic platform that identifies proteins and complexes amenable to coupling, we revealed 171 targetable protein classes, including mutant‑selective complexes and assemblies not traditionally addressed by small molecules. We then optimized a COUPLr against the oncogenic fusion EML4‑ALK. This compound engages EML4‑ALK by binding its EML4 domain, remodeling protein dynamics, disrupting downstream signaling, and inducing proteasome‑mediated degradation of the fusion. Finally, we show that FDA‑approved drugs can be converted into COUPLrs to degrade their targets, indicating that this modality can endow existing therapeutics with new functional properties. Overall, molecular COUPLrs offer an unbiased framework to discover, characterize, and pharmacologically exploit protein complexes.
Authors
- Emily E. Ackerman (ORCID: https://orcid.org/0000-0003-0735-7152)
- Diane Yang (ORCID: https://orcid.org/0000-0002-2229-0622)
- Stefan Harry
- Huan Yee Koh (ORCID: https://orcid.org/0000-0002-0488-2616)
- Liron Bar‐Peled (ORCID: https://orcid.org/0000-0003-2687-9546)
- Toshio Fujino (ORCID: https://orcid.org/0000-0002-3640-3472)
- Siwen Zhang (ORCID: https://orcid.org/0009-0009-3994-5152)
- Natalie Shannon Nordenfelt (ORCID: https://orcid.org/0000-0002-3484-029X)
- Sirano Dhe‐Paganon (ORCID: https://orcid.org/0000-0003-0824-5929)
- Zhenyu Sun (ORCID: https://orcid.org/0000-0001-7527-6026)
- Brian B. Liau (ORCID: https://orcid.org/0000-0002-2985-462X)
- Stefan T. Kaluziak (ORCID: https://orcid.org/0000-0002-7531-2602)
- M Lazarov
- Gregory J. Heffron
- Edwin Zhang
- A. John Iafrate (ORCID: https://orcid.org/0000-0002-7888-4067)
- Nicholas J. Chen (ORCID: https://orcid.org/0000-0002-7975-2787)
- Mariko Takahashi (ORCID: https://orcid.org/0000-0003-2465-7907)
- Maolin Ge (ORCID: https://orcid.org/0000-0002-8803-1463)
- Mohammed Mahamdeh (ORCID: https://orcid.org/0000-0003-3985-6992)
- Hyuk‐Soo Seo (ORCID: https://orcid.org/0000-0003-0646-2102)
- Harrison B. Chong (ORCID: https://orcid.org/0000-0003-0880-089X)
- Vivek Naranbhai (ORCID: https://orcid.org/0000-0003-4281-8882)
- Radosław P. Nowak (ORCID: https://orcid.org/0000-0002-0605-0071)
- Neha Khandelwal (ORCID: https://orcid.org/0000-0001-7831-6820)
- Roy J. Soberman (ORCID: https://orcid.org/0000-0002-2817-0517)
- Aaron N. Hata (ORCID: https://orcid.org/0000-0002-6127-318X)
- Maristela L. Onozato (ORCID: https://orcid.org/0000-0003-2619-1848)
- George Popoola
- Idris A Barakat (ORCID: https://orcid.org/0009-0006-6434-6109)
- Jan Gerhartz (ORCID: https://orcid.org/0009-0002-9457-4656)
- Wenxin Yang (ORCID: https://orcid.org/0009-0006-9141-367X)
- Dawn Mitchell
- Zavontae Holmes
- Zander Chearavanont
- Kim Emonds
- Samay Trivedi
- Elizabeth Codd
- Giovan McKnight
- Chengzhuo Gao
- Magdy Gohar
- Reilly Stevens
- Anastasia Ignashkina
- Herman Xin Yang. Leong (ORCID: https://orcid.org/0009-0001-5603-9129)
- Christine Lee (ORCID: https://orcid.org/0009-0002-4971-3266)
- Abigail Elizabeth. Smith (ORCID: https://orcid.org/0000-0002-0252-927X)
- Alexander Daniel. Carlin (ORCID: https://orcid.org/0000-0002-1821-4694)
- Sufian Moawiyah. Ibrahim (ORCID: https://orcid.org/0009-0001-5746-3992)
- Paul Strickland. Mullin (ORCID: https://orcid.org/0009-0001-1043-4393)
- Christopher J. Ott (ORCID: https://orcid.org/0000-0001-6142-7241)
- Hector Martinez. Luna (ORCID: https://orcid.org/0009-0003-7171-7981)
Institutions
- University of Bonn (DE)
- Harvard University Press (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Monash University (AU)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-07-27
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-2314
- Citations
- 4
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00