{"id":16894,"date":"2025-11-10T19:09:15","date_gmt":"2025-11-10T19:09:15","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/do-ligands-dream-of-degrader-fame-rapid-direct-to-biology-generation-of-protacs\/"},"modified":"2025-11-10T19:09:15","modified_gmt":"2025-11-10T19:09:15","slug":"do-ligands-dream-of-degrader-fame-rapid-direct-to-biology-generation-of-protacs","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/do-ligands-dream-of-degrader-fame-rapid-direct-to-biology-generation-of-protacs\/","title":{"rendered":"Do Ligands Dream of Degrader Fame? Rapid Direct-to-Biology generation of PROTACs!"},"content":{"rendered":"

PROTACs, formally known as heterobifunctional degraders, remain an exciting modality for tackling disease-linked proteins long considered \u201cundruggable.\u201d By inducing the degradation of disease-causing proteins, degraders open a therapeutic route where traditional, occupancy-based inhibitors show limited efficacy or face other challenges.<\/span><\/p>\n

While the first wave of bifunctional degraders focused heavily on oncology, the scope is now broadening across the industry to include autoimmune and neurodegenerative indications.<\/span><\/p>\n

To accelerate discovery, direct-to-biology (D2B) approaches have been developed that omit purification of synthesized compounds and test crude reaction mixtures directly for activity. This enables miniaturization, greatly increases throughput, reduces reagent use, and shortens cycle times. Crucially, crude mixtures must also be monitored for toxicity to discard that any apparent degrader hit is not due to non-selective cell-killing.<\/span><\/p>\n

At Sygnature Discovery, we have extended our CHARMED platform for degrader discovery to include a D2B module. As a case study, we deployed our D2B-CHARMED platform to generate degraders targeting the kinase LRRK2. Mutations in LRRK2 are linked to familial Parkinson\u2019s disease (PD), and LRRK2 is a validated PD target. Because LRRK2 also exerts non-catalytic functions (e.g. scaffolding), kinase inhibition alone does not fully address all its functionalities, however protein removal via induced degradation does.<\/span><\/p>\n

This therapeutic concept is gaining traction with recently reported<\/a> Phase 1 SAD\/MAD data from Arvinas in human volunteers and Parkinson\u2019s patients, showing (1<\/a>) dose-dependent drug increase in\u00a0 plasma and CSF (ii) evidence of target engagement (LRRK2 reductions in PBMCs and in CSF), and (iii) CSF proteomic analysis demonstrating modulation of lysosomal and microglial pathways relevant to neurodegenerative diseases.<\/span><\/p>\n

In our study, we combined three known LRRK2 ligands with our CHARMED library of ligase-recruiters pre-coupled to linkers to rapidly generate just over 300 bifunctional molecules. Excitingly, activity screening identified compounds with nanomolar degrader potency (pending further validation), demonstrating the utility of the approach.<\/span><\/p>\n

Download our poster to learn more about the CHARMED D2B approach for LRRK2! (Available here<\/a> on Nov. 16th, following its Neuroscience 2025 disclosure)<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":13645,"template":"","category":[1413,817,820,818,822],"class_list":["post-16894","blog","type-blog","status-publish","has-post-thumbnail","hentry","category-direct-to-biology","category-domaines-therapeutiques","category-modalites","category-neuroscience","category-tpd"],"acf":[],"yoast_head":"\nDo Ligands Dream of Degrader Fame? 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