{"id":14179,"date":"2026-05-06T14:57:53","date_gmt":"2026-05-06T13:57:53","guid":{"rendered":"https:\/\/www.blopig.com\/blog\/?p=14179"},"modified":"2026-05-06T16:03:07","modified_gmt":"2026-05-06T15:03:07","slug":"a-first-for-protacs","status":"publish","type":"post","link":"https:\/\/www.blopig.com\/blog\/2026\/05\/a-first-for-protacs\/","title":{"rendered":"A first for PROTACs"},"content":{"rendered":"\n

Last week marked a major milestone in small-molecule drug discovery with the first FDA approval of a proteolysis targeting chimera (PROTAC). After a modest but successful phase 3 clinical trial demonstrated a 2.9 month improvement in median progression free survival1<\/a><\/sup> for a type of advanced breast cancer1<\/sup>, the FDA has approved Veppanu (vepdegestrant), co-developed by Arvinas and Pfizer, as the first PROTAC protein degrader therapy2<\/sup>. So what is a PROTAC?<\/p>\n\n\n\n\n\n\n\n

Traditional small-molecule drugs operate by selectively binding to a target, typically a protein, and modifying its function. Broadly, these modifications can be categorized as inhibitory or activating. Drugs that function as inhibitors <\/strong>serve to reduce <\/strong>the function of a target, often an enzyme, receptor, transporter, or signalling protein. For example, if an enzyme is overactive in cancer, inflammation, or viral replication, an inhibitor can slow or block that disease-driving process. In contrast, an activator <\/strong>increases the function of a target. Activators are used when a disease involves insufficient activity<\/strong>, loss of signalling, weak enzyme function, or impaired cellular response. Activators can operate by increasing enzyme turnover, stabilizing an active protein conformation, enhancing receptor signalling, or boosting downstream pathway output.<\/p>\n\n\n\n

Since the early 2000s, however, an advanced wave of targeted protein degradation therapies have been under development3<\/sup>. Rather than inhibiting a target, targeted degradation therapies operate by leveraging the body’s natural cellular machinery, the proteasome, to degrade <\/strong>the target.<\/p>\n\n\n\n

PROTACs consist of three parts: an E3 ligand, a linker, and a warhead that attaches to a protein of interest (POI) 4<\/sup>. At a high-level, a PROTAC aims to recruit a protein called an E3 ligase to be within close proximity to the POI. This is achieved by creating a bridge between the E3 ligase and the POI using the E3 ligand, a warhead that attaches to the POI, and a linker which bridges them. The E3 ligase mediates the transfer of ubiquitin to the POI, and these ubiquitin tags mark the POI for degradation by the proteasome, a complex which degrades proteins4<\/sup>. A figure from a recent review paper4<\/sup> illustrates:<\/p>\n\n\n\n

\"\"<\/a><\/figure>\n\n\n\n

But if we have inhibitors, which ostensibly reduce the function of the target, why would we want to go to the trouble of degrading it entirely? PROTACs come with a number of advantages over traditional inhibitors. For example, in certain cases, the presence or accumulation of a protein is what contributes to disease pathology. Thus, PROTACs are useful when when the target has nonenzymatic\/scaffolding functions that an inhibitor may not block. Moreover, PROTACs can work on proteins that are hard to inhibit. For example, some proteins lack a deep, druggable active site. In contrast, to be effective, a PROTAC only needs to bind the target somewhere productively; the binding event does not necessarily have to inhibit function directly.<\/p>\n\n\n\n

Last week’s approval of Veppanu demonstrates that PROTACs are clinically viable drugs, and more generally signals that targeted protein degradation has a future in the quest to combat disease. Similar therapeutics such as ATTECs, AUTACs and LYTACs, which hijack cellular autophagy machinery via the lysosome5<\/sup>, now seem increasingly promising as future modalities for small-molecule drugs. Similarly, this news should serve as encouragement that other advanced small-molecule therapeutics such as molecular glues6<\/sup> may also not be too far from the clinic.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

    \n
  1. Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer, New England Journal of Medicine (Campone et al, 2025)<\/li>\n\n\n\n
  2. Arvinas Announces FDA Approval of VEPPANU (vepdegestrant)<\/a><\/li>\n\n\n\n
  3. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation, Proceedings of the National Academy of Sciences (Sakamoto et al, 2001)<\/li>\n\n\n\n
  4. PROTAC targeted protein degraders: the past is prologue, Nature Reviews Drug Discovery, (B\u00e9k\u00e9s et al, 2022).<\/li>\n\n\n\n
  5. Emerging New Concepts of Degrader Technologies, Trends in Pharmacological Science, (Ding et al, 2020)<\/li>\n\n\n\n
  6. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Biochemistry, (Sasso et al, 2022)<\/li>\n<\/ol>\n\n\n\n

    Footnotes<\/strong><\/p>\n\n\n

    1. Relative to the hormone treatment fulvestrant. \u21a9\ufe0e<\/a><\/li><\/ol>\n\n\n

      <\/p>\n","protected":false},"excerpt":{"rendered":"

      Last week marked a major milestone in small-molecule drug discovery with the first FDA approval of a proteolysis targeting chimera (PROTAC). After a modest but successful phase 3 clinical trial demonstrated a 2.9 month improvement in median progression free survival for a type of advanced breast cancer1, the FDA has approved Veppanu (vepdegestrant), co-developed by […]<\/p>\n","protected":false},"author":143,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"nf_dc_page":"","wikipediapreview_detectlinks":true,"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"ngg_post_thumbnail":0,"_jetpack_memberships_contains_paid_content":false,"footnotes":"[{\"id\":\"3d98b188-405a-4692-b189-c41b63e1b77a\",\"content\":\"Relative to the hormone treatment fulvestrant.\"}]"},"categories":[849,201],"tags":[],"ppma_author":[905],"class_list":["post-14179","post","type-post","status-publish","format-standard","hentry","category-drug-discovery","category-small-molecules"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"authors":[{"term_id":905,"user_id":143,"is_guest":0,"slug":"acer","display_name":"Acer Blake","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/16d2b2e0c9160f30f99612c3b7f2ba1b106f3001f03a703d69f079f0b5bbc121?s=96&d=mm&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/14179","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/users\/143"}],"replies":[{"embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/comments?post=14179"}],"version-history":[{"count":5,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/14179\/revisions"}],"predecessor-version":[{"id":14192,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/posts\/14179\/revisions\/14192"}],"wp:attachment":[{"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/media?parent=14179"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/categories?post=14179"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/tags?post=14179"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.blopig.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=14179"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}