{
  "id": 3746355,
  "title": "Expanding the Ligandable Chemical Space of OTUB1 through Discovery of a Four-Membered-Ring Recruiter Chemotype",
  "url": "https://urgent.news/2026/08/27/expanding-the-ligandable-chemical-space-of-otub1-through-discovery-of",
  "topic": "science",
  "section": "Science",
  "published": "2026-08-27T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.26.747398v1?rss=1"
  },
  "original_language": "en",
  "account": "Deubiquitinase-targeting chimeras, or DUBTACs, have shown potential for targeted protein stabilization, although their wider use is constrained by the limited number of ligandable deubiquitinase recruiters. In a recent study, researchers identified a novel four-membered-ring OTUB1 recruiter chemotype that could potentially overcome this limitation. Through extensive structure-activity relationship studies, they discovered compound 21 (MS2159) as a highly effective and selective covalent OTUB1 ligand. Biochemical and intact protein mass spectrometric tests revealed that MS2159 specifically targets the non-catalytic C23 residue of OTUB1 while remaining inactive on other proteins, and importantly, it does not impair OTUB1's deubiquitinase activity. Furthermore, when MS2159 was linked to the CFTR ligand lumacaftor, it produced compound 25 (MS2134), which successfully stabilized the {Delta}F508-CFTR variant. These findings not only introduce a new OTUB1 recruiter scaffold but also broaden the ligandable chemical space of OTUB1, paving the way for the development of next-generation DUBTACs.",
  "summary": "Deubiquitinase-targeting chimeras (DUBTACs) have emerged as a promising strategy for targeted protein stabilization, but their broader application remains limited by the scarcity of ligandable deubiquitinase recruiters. Here, we report a previously unexplored four-membered-ring OTUB1 recruiter chemotype. Through systematic structure-activity relationship studies, we identified compound 21…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 2,
    "also_reported_by": [
      {
        "outlet": "Phys.org",
        "title": "Discovery reveals rapid pathways to complex aromatic molecules in space",
        "url": "https://urgent.news/2026/08/27/discovery-reveals-rapid-pathways-to-complex-aromatic-molecules-in",
        "published": "2026-08-27T22:30:02.000Z"
      }
    ]
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}