DCAF16

PRESS RELEASE Amphista Therapeutics unveils new differentiated mechanism of action for BRD9 degradation at 2024 Protein Degradation in Focus Symposium First presentation of a novel mechanism of action for the degradation of BRD9 – completely differentiated from cereblon- or VHL-based PROTACs Amphista’s bifunctional BRD9 degraders selectively induce BRD9 to DCAF16 proximity and serve as molecular glues, leading to strong and rapid degradation of BRD9 Discovery further underscores Amphista’s proprietary chemistry and high-quality science which is being applied to the discovery and development of additional targeted glues beyond BRD9 Cambridge, UK, May 23, 2024 – Amphista Therapeutics (“Amphista”), a leader in next generation targeted protein degradation (TPD) approaches, today announces the unveiling of a new mechanism of action for the degradation of BRD9, an emerging target in oncology, that is differentiated from cereblon- or VHL-based PROTACs, during an oral presentation at the 2024 Protein Degradation in Focus Symposium held in Dundee, UK. This significant news for the TPD field builds upon an earlier announcement by Amphista of two compelling data sets demonstrating in vivo efficacy and central nervous system (CNS) activity of its mechanistically differentiated protein degraders. At today’s presentation titled “Degradation of BRD9 by a novel targeted glue”, Dr Andrea Testa, Scientific Co-Founder and Senior Director, Discovery Chemistry showed data from proteomic and genetic validation studies which demonstrate that Amphista’s bifunctional degraders induced degradation of BRD9 by target-assisted E3 ligase recruitment. This novel mechanism selectively induces the proximity of BRD9 to DCAF16 and serves as a molecular glue. DCAF16 is a cullin-RING E3 ligase which can facilitate degradation of proteins of interest via ternary complex formation. Induction of this complex leads to deep and rapid degradation of BRD9 in vivo. Louise Modis, Chief Scientific Officer of Amphista Therapeutics, said: “The discovery of a novel mechanism for BRD9 degradation, differentiated from cereblon- or VHL-based PROTACs, is a testament to Amphista’s proprietary chemistry and know-how. Our ability to translate this novel approach into high-quality, drug-like compounds with oral bioavailability and activity in vivo is truly exciting. As we continue to spearhead our efforts to advance new TPD approaches, our goal remains clear – to expand the offering of TPD medicines beyond CRBN and VHL-based agents and bring effective treatments to patients in areas of high unmet need.” In the results presented, Amphista’s sub-nanomolar BRD9 degraders showed activity in both solid and liquid cancer cell lines and demonstrated a high degree of selectivity over 8,000 proteins quantified by proteomics, including the closely related proteins BRD7 and BRD4. Notably, these compounds induced BRD9 degradation in a mouse xenograft model illustrating Amphista’s BRD9 degraders are orally bioavailable and active in vivo. This is the first-time in vivo degradation of BRD9 has been demonstrated via DCAF16, underscoring the potential therapeutic application of Amphista’s bifunctional degraders. Building on this knowledge, Amphista is applying its proprietary scientific know-how and expertise to the development of targeted glues which induce degradation of different targets, expanding the opportunity beyond BRD9. Future announcements will provide details of additional pipeline targets as part of Amphista’s ambitions to develop a first- and/or best-in-class portfolio of degraders with leading physicochemical properties. About Amphista Therapeutics Amphista Therapeutics is focused on transforming the lives of patients with severe diseases, including cancer and neurodegenerative disease, through the advancement of next generation targeted protein degradation (TPD) medicines. Amphista is applying its proprietary warhead chemistry and mechanistic know-how to generate bifunctional targeted glues with a differentiated mechanism and leading physicochemical properties. Its portfolio offers the potential for first- and/or best-in-class assets and expanding the offering of TPD medicines beyond CRBN and VHL-based agents. Founded by Advent Life Sciences, Amphista is a spin-out of TPD expert Professor Alessio Ciulli’s laboratories at the University of Dundee. Amphista is funded by leading life science investors including Forbion, Gilde Healthcare, Novartis Venture Fund, Advent Life Sciences, Eli Lilly & Company and The Dementia Discovery Fund, and also has strategic collaborations with Bristol Myers Squibb and Merck. For more information, please visit: Amphista and the Amphista logo are all trademarks or registered trademarks of Amphista Therapeutics Limited. For more information please contact: ICR Consilium Amber Fennell, Namrata Taak Email: Amphista@consilium-comms.com Tel: +44 (0)20 3709 5813