Nineteenth Annual Discovery on Target Meeting

Cambridge Healthtech Institute held its annual Discovery on Target meeting last week. For the first time the event was hybrid, with slightly fewer than half the attendees in Boston and the rest online, and I’m happy to report that it was quite successful. In-person attendees were required to show proof of vaccination against COVID-19, and masks and social distancing guidelines were observed. Ten of the individual tracks were hybrid, while four were virtual only. However, even in these cases it was valuable to attend in person; after one vendor presentation I immediately went from my hotel room to the exhibit hall to find out more.

 

For many of us this was the first in-person conference we had attended in nearly two years, and the return to some semblance of normalcy. At the same time, the fact that in-person talks were broadcast opened the conference to people unable to travel. One of the most active Q&A participants in one track was in Singapore, despite the 12 hour time difference.

 

Another nice feature of the virtual or hybrid model is reduction in FOMO; if you find it difficult to choose between the seven concurrent talks you can watch some later. But, as our 2020 poll showed, speakers may be less forthcoming with newer, more speculative results in a recorded format.

 

With the heavy focus on biology there seemed to be fewer “conventional” fragment stories, though Lars Neumann (Proteros) did discuss the identification and optimization of a kinase inhibitor that does not interact with the hinge region. Novel targets were represented in work from Harald Schwalbe (Johann Wolfgang Goethe University), who described fragment screens against RNA; I’ll post more on this later this month.

 

We’ve previously discussed the COVID Moonshot Consortium to rapidly discover drugs for SARS-CoV-2. Annette von Delft (Oxford University) provided an update, noting that fragments from a crystallographic screen have been advanced to compounds with mid-nanomolar biochemical and cellular activity. DMPK properties are reasonable, though this is an area of continued optimization. Annette mentioned the goal is to enter clinical development in 2023. Progress has been accelerated by the crowd-sourced nature of the initiative, with nearly 40 groups and 150 individuals working together. She also noted that many of the molecules are active against other coronaviruses.

 

The main series being advanced by the COVID Moonshot are noncovalent inhibitors of the SARS-CoV-2 main protease M^Pro. However, covalent molecules against this target are also moving forward. Matthew Reese described Pfizer’s oral PF-07321332, which is currently in several phase 3 trials. The program began on March 16 of last year and the clinical compound was first synthesized just four months later. Clinical trials began in February of this year, a mere 11 months after the program began. This is astonishingly rapid, though the researchers did benefit from previous work on SARS-CoV-1 and even earlier work from the 1990s on rhinovirus inhibitors. It is worth re-reading Glyn Williams’ 2020 discussion of HIV protease inhibitors for more historical context and insights.

 

Although PF-07321332 did not come from FBLD, fragments capable of forming covalent bonds were well represented. We’ve previously discussed fully-functionalized fragments (FFFs, or PhABits), which in addition to having a photoreactive group also contain an alkyne handle so that any target they bind can be captured and identified. Aarti Kawatkar and Jenna Bradley described using these at AstraZeneca to identify new targets. They’ve constructed a library of just under 500 FFFs and are using these to do phenotypic screening, particularly in hard-to-get cells such as primary tissue samples. They are also making the FFF library available through their open innovation initiative.

 

Fully functionalized fragments are just one flavor of covalent fragments. Indeed, unlike the light-activated warhead of FFFs, most covalent fragments have a moiety that reacts selectively with amino acid residues such as cysteines. Steve Gygi (Harvard) and Dan Nomura (UC Berkeley) both described covalent screening in cells to identify starting points against challenging targets. The approach is also gaining traction in industry; Heather Murrey described how Scorpion is using covalent fragments, and noted that Vividion (mentioned here) was recently acquired by Bayer for up to $2 billion.

 

A prominent recent success story from covalent fragments is sotorasib, which was approved earlier this year to treat certain non-small cell lung cancer patients whose tumors carry the G12C mutant form of KRAS. Sotorasib binds to a mostly cryptic pocket, and the protein itself has low ligandability. To improve the odds of finding new fragments, Mela Mulvihill described how she and her colleagues at Genentech have developed antibodies that stabilize the so-called Switch II loop in an “open” conformation more accessible to small molecules. An SPR-based fragment screen in the presence of the antibody led to more than twice as many hits, many of which could bind more tightly than without the antibody. Darryl McConnell (Boehringer-Ingelheim) also described using fragment-based methods to pursue KRAS, including mutants other than G12C.

 

In addition to inhibitors, Darryl also described bifunctional molecules that selectively cause degradation of KRAS by bringing it to the proteasome via E3 ligases. In his opinion PROTACs are “the best thing since sliced bread.” PROTACs and targeted protein degradation were in fact the subject of two tracks that spread across all three days of the conference, and were also covered in a pre-conference short course taught by Stewart Fisher (C4 Therapeutics) and Alexander Statsyuk (University of Houston). Here too fragments are playing an increasing role; in a second talk Dan Nomura described how he has been using chemoproteomic fragment approaches to identify ligands for E3 ligases.

 

The recent excitement around PROTACs is probably justified, but as our post last week noted, new technologies are not necessarily fast or inevitable. PROTACs were first described in 2001; Adam Gilbert (Pfizer) puckishly described them as a “20-year overnight success story.” But by the end of this year there will be roughly a dozen PROTACs in the clinic, with more likely to join them soon.

 

I’ll end on this positive note, but welcome your thoughts on science or experience with hybrid conferences. I look forward to seeing you at one in the near future!