{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:20:11Z","timestamp":1788337211678,"version":"build-2803163510"},"reference-count":157,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Chongqing, China","award":["CSTB2023NSCQ-MSX0740"],"award-info":[{"award-number":["CSTB2023NSCQ-MSX0740"]}]},{"name":"Entrepreneurship and Innovation Support Plan of Chongqing for Returned Overseas Scholars","award":["2305013383486448"],"award-info":[{"award-number":["2305013383486448"]}]},{"name":"Entrepreneurship and Innovation Support Plan of Chongqing for Returned Overseas Scholars","award":["2508013605744353"],"award-info":[{"award-number":["2508013605744353"]}]},{"name":"National Training Program of Innovation and Entrepreneurship for Undergraduates","award":["202610631028"],"award-info":[{"award-number":["202610631028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Chemically induced proximity (CIP) has revolutionized small-molecule pharmacology by moving beyond traditional occupancy-based inhibition and activation. Within this paradigm, monovalent nondegrading molecular glues (ndMGs) represent a structurally compact and mechanistically distinct class of linkerless compounds. These agents stabilize or induce selective biomolecular interactions, altering the functional state or cellular localization of macromolecular complexes without causing component degradation. Once considered rare phenomena unique to specific natural products, ndMGs are now being actively engineered across diverse therapeutic landscapes, with multiple candidates advancing into clinical trials and achieving regulatory validation. We systematically highlight their evolving capabilities to modulate oncogenic networks, intervene with immune activity, rectify metabolic signaling, control neurodegenerative trafficking and stress networks, and disrupt critical pathogen assemblies, while broadening the druggable landscape into non-canonical mechanisms. In each section, we analyze the therapeutic value of the targets, the molecular mechanisms of action, the latest progress, and the unique challenges faced by these strategies. In summary, the ndMG modality represents a highly versatile strategy to unlock the undruggable proteome.<\/jats:p>","DOI":"10.3390\/ph19091388","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:53:11Z","timestamp":1788335591000},"page":"1388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6185-4999","authenticated-orcid":false,"given":"Linfeng","family":"Li","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"},{"name":"Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-9297","authenticated-orcid":false,"given":"Yuying","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaao5902","DOI":"10.1126\/science.aao5902","article-title":"Chemically induced proximity in biology and medicine","volume":"359","author":"Stanton","year":"2018","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1126\/science.add7574","article-title":"Molecular glue CELMoD compounds are regulators of cereblon conformation","volume":"378","author":"Watson","year":"2022","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41392-022-00966-4","article-title":"Targeted protein degradation: Mechanisms, strategies and application","volume":"7","author":"Zhao","year":"2022","journal-title":"Signal Transduct. 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