Discovery by Shanghai scientists inspires new plan of ATTEC for protein degradation
In a review penned weeks ago, Craig Crews — the Yale scientist credited with the discovery of PROTACs — reflected on how, in the two decades since he helped launch the field, targeted protein degradation has moved beyond the proteasome into “novel and exciting” strategies.
“For example, Lysosome Targeting Chimeras (LYTACs) harness the lysosomal degradation pathway to induce degradation of extracellular proteins and the Macroautophagy Degradation Targeting Chimera (MADTAC) platforms, AUTACs and ATTECs hijack the autophagy pathway, thus potentially enabling the targeted destruction of entire organelles and protein aggregates,” he and co-author Michael Bond wrote.
One of those approaches they spotlighted is now having a coming-out party.
Sherpa Healthcare Partners is leading the $30 million Series A for PAQ Therapeutics, which is promising to chart a different route for degrading disease-causing substrates.
CEO Nan Ji was head of chemistry at Kymera, the Atlas-backed startup whose take on protein degradation would lead into a Sanofi partnership, when he noticed a paper in Nature describing autophagosome-tethering compounds, or ATTECs, in late 2019. While the degraders he had been working on leveraged the ubiquitin-proteasome system (UPS), the authors went with the other major degradation pathway: autophagy, which literally means “self-eat.”
Specifically, the researchers figured out a way to appropriate the process by which a vesicle engulfing certain substrates, dubbed autophagosome, is formed. By pulling together an autophagosome structure and a disease-causing substrate, they could nudge the autophagosomes to gobble up those problematic molecules, in their case the protein to blame for Huntington’s disease. A good visualization exercise may be the game of Pac-Man, with the little yellow PAC head chewing up all the dots — at least that’s where PAQ would eventually get its name.
“Because autophagy is the most versatile mechanism in the human body to initiate degradation, it actually has a much wider variety of substrates that it can take care of, such as lipids, such as protein aggregates, defective mitochondria,” Nan Ji told Endpoints News.
He wasn’t alone. Coincidentally, Nest.Bio Ventures and Matrix Partners China saw potential in that technology and got in touch with the scientists at Shanghai’s Fudan University who wrote the paper to seed a spinout.
“So in that sense, this company actually speaks to the growing presence of the scientific discovery from China,” he said, adding that Boxun Lu, the scientific co-founder, “actually is trained in the US, at UPenn, and then he did his postdoc at Novartis.”
Ji, who shares a similar background (he got his bachelor’s at Peking University before pursuing a PhD at Harvard), was recruited to be CEO about a year ago.
As the protein degradation space booms, diversity is also growing. Intrigued by the possibility of completely flushing out, and not just blocking, mutant or excessive molecules that cause disease, Big Pharma and VCs have wagered big on all sorts of new technologies. Some players are staking their names on new E3 ligases while others bank on different ways to recruit the proteins for disposal, such as molecular glues or monovalent binders. Carolyn Bertozzi and Versant have teamed up at Lycia Therapeutics to pursue LYTACs, which leverages the lysosome to degrade extracellular proteins (whereas PROTACs can only get rid of intracellular ones).
Working with a small team of six in the Boston/Cambridge area, Ji thinks of the company as global with a network of CRO and three scientific advisors: David Rubinsztein, professor of molecular neurogenetics at the University of Cambridge; Jared Rutter, a cancer researcher at the University of Utah; and Jin-Quan Yu at Scripps.
The Series A cash, which also came from Huagai Capital, MSA Capital and MRL Ventures Fund, is expected to push the lead candidate for an unspecified genetic neurodegenerative disorder into preclinical development. Two other programs are being lined up, and the hope is to be in the clinic within three years. But Ji is also realistic.
“We do expect there are gonna be challenges along the way,” he said. “We have to build assays, we have to build know-hows. It could take us longer but we are ready.”