Amphista Therapeutics reveals novel BRD9 degradation mechanism at 2024 Symposium

Amphista Therapeutics, a pioneering company in the field of targeted protein degradation (TPD), recently introduced a groundbreaking new mechanism for the degradation of BRD9, a promising target in oncology. This announcement was made during an oral presentation at the 2024 Protein Degradation in Focus Symposium held in Dundee, UK.

The novel mechanism presented by Amphista is distinct from the commonly used cereblon- or VHL-based PROTACs. Amphista’s approach involves bifunctional BRD9 degraders that selectively bring BRD9 into close proximity with DCAF16, a cullin-RING E3 ligase. This interaction serves as a molecular glue, leading to the efficient and rapid degradation of BRD9. The discovery highlights Amphista’s advanced chemistry capabilities and its commitment to discovering new targeted glues beyond BRD9.

Dr. Andrea Testa, Scientific Co-Founder and Senior Director of Discovery Chemistry at Amphista, shared data from proteomic and genetic validation studies during the presentation titled “Degradation of BRD9 by a novel targeted glue.” These studies demonstrated that Amphista’s bifunctional degraders induce BRD9 degradation through target-assisted E3 ligase recruitment. The process specifically induces BRD9 to form a complex with DCAF16, which facilitates the breakdown of the protein, showcasing deep and rapid degradation of BRD9 in vivo.

Louise Modis, Chief Scientific Officer of Amphista Therapeutics, emphasized the significance of this novel discovery. Modis stated, “The identification of a unique mechanism for BRD9 degradation, distinct from cereblon- or VHL-based methods, underscores Amphista’s proprietary chemistry and expertise. Our ability to create high-quality, drug-like compounds with oral bioavailability and in vivo activity is very promising. As we continue to lead our efforts in advancing new TPD approaches, our objective is to broaden the range of TPD medicines beyond CRBN and VHL-based agents, providing effective treatments for patients with significant unmet needs.”

In the presented results, Amphista’s sub-nanomolar BRD9 degraders exhibited activity in both solid and liquid cancer cell lines and showed a high degree of selectivity over 8,000 proteins, including closely related proteins like BRD7 and BRD4. Importantly, these compounds induced BRD9 degradation in a mouse xenograft model, demonstrating their oral bioavailability and effectiveness in vivo. This marks the first instance of in vivo degradation of BRD9 via DCAF16, highlighting the therapeutic potential of Amphista’s bifunctional degraders.

Amphista Therapeutics is leveraging this discovery to develop additional targeted glues that induce the degradation of various proteins, aiming to expand its pipeline beyond BRD9. The company plans to announce further details about new targets in its portfolio, which aims to include first- and/or best-in-class degraders with leading physicochemical properties.

Amphista Therapeutics, founded by Advent Life Sciences, is dedicated to improving the lives of patients with severe diseases such as cancer and neurodegenerative disorders through innovative TPD medicines. The company’s proprietary warhead chemistry and mechanistic insights enable the generation of bifunctional targeted glues with unique mechanisms and superior properties. Amphista's portfolio has the potential to offer first- and/or best-in-class assets, expanding the landscape of TPD medicines beyond existing CRBN and VHL-based approaches.

Amphista is backed by prominent life science investors, including Forbion, Gilde Healthcare, Novartis Venture Fund, Advent Life Sciences, Eli Lilly & Company, and The Dementia Discovery Fund. Additionally, the company has strategic collaborations with Bristol Myers Squibb and Merck.

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