Watertown Bio Journal Club: Engineering Plastic Eating- and Concrete Laying Bacteria
Plus, How to design a PROTAC
Watertown Bio Journal Club is a monthly publication highlighting the scientific research produced by labs in Watertown. If you’re a Watertown-based biotech and have a recently published article, pre-print, or conference publication you would like featured in our next issue, reach out at newsletter@watertown.bio. If you enjoy our publications consider supporting us.
Featured Article: Discovery of CFT8634, a Potent, Selective, and Orally Bioavailable Heterobifunctional Degrader of BRD9
In this article published in the Journal of Medicinal Chemistry, C4 Therapeutics describes their novel BRD9 PROTAC, from initial designs, to medicinal chemistry and optimization, to pharmacokinetic profiling, to clinical PK/PD, Efficacy and Safety in a phase 1 clinical trial. The CFT8634 PROTAC was motivated by observations that shRNA knockdown of the transcription factor BRD9 in SMARCB1-perturbed synovial sarcomas stopped tumor cell proliferation. A similar rationale was used by Foghorn Therapeutics (who just moved to Watertown) to develop their BRD9 PROTAC FHD-609 which was published earlier this year.
The paper covers a lot of ground, and serves a good overview of the factors that go into the design of a PROTAC, given the large chemical space that can be explored with the combination of the BRD9 targeting domain and the linker domain, and the multiple rounds of in vitro and in vivo optimization steps for both degrader performance and favorable pharmacokinetics. Ultimately, this process produced CFT8634 which demonstrated strong, specific BRD9 degradation and tumor growth arrest in both Yamato-ss and patent-derived xenograft mouse tumor models.
Unfortunately, the paper also serves as a reminder of the limitations of preclinical animal models: in both C4 and Foghorn’s clinical trials only partial therapeutic responses were observed for patients with synovial sarcoma. There were also some concerning T-wave abnormalities and QT prolongation cardiac toxicities observed in human participants, but not in the preclinical safety studies. These safety concerns ultimately lead both C4 and Foghorn to halt the development of their respective BRD9 degrader programs. It would be an interesting research project to explore the source of the BRD9 cardiac toxicities in human iPSC or organoid models and do some comparative biology across human, rat and mouse cardiac models to understand why these toxicities didn’t appear in the preclinical animal studies.
Featured Preprints: Functional genomics in a microbe that degrades and metabolizes PET plastic and A genetic platform for a biocementation bacterium
In these two preprints Cultivarium demonstrates the utility of their POSSUM toolkit to develop plasmids for manipulating two previously intractable bacterial organisms: Piscinibacter sakaiensis which can degrade PET plastics (blog post), and Sporosarcina pasteurii which can mineralize urea into calcium carbonate around loose aggregates to form more solid, cement-like material (blog post). In both works, the group was able to develop cellular biology techniques to modify the organisms either to knock out the important functional genes, or to screen a mutant library of the functional enyzme to find variants that could more quickly degrade PET or more quickly mineralize urea to form biocement. While these pre-prints are only the first steps in working with these organisms, its possible to see future collaborations with other Watertown firms like the enzyme design and optimization lab at Pando Bio or the synthetic biologists and industrial chemists at Modular Genetics that could advance these findings towards commercialization.
Quick Hits:
Cultivarium also released a pre-print detailing their new platform for automating DNA electrification into novel bacteria. It would be interesting to compare their platform’s success with fellow Watertown company Portal Bio’s mechanoporation platform.
At ASH 2025, Disc Medicine presented two posters, one on their Phase 2 trial of Disc-3405 for Polycythemia Vera, and the other on their Phase 2 trial of Disc-0974 for Myelofibrosis and Anemia.
Also at ASH, Diagonal Therapeutics presented a poster on their prospective natural history study of hereditary hemorrhagic telangiectasia patients, which will inform the study design for the clinical trials of their lead compound DIAG723.
At the FLORetina-ICOOR Meeting Eyepoint Pharmaceuticals presented updates on their lead EYP1901 therapeutic and its ongoing Phase 3 Trial for wet AMD, updates to their Phase 2 trial for wet AMD and Phase 2 trial results for Diabetic Macular Edema.
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