Screening cascade - fast track and regular track of designs

We’ll be sharing our screening workflow in the next few days (Ed has drafted Target Product Profiles (TPPs)). Our workflow will comprise a regular track and a fast track to maximise the speed of finding a lead candidate.

Fast track: After the second call closes, we will select up to 10 particularly exciting compounds from the 1st and 2nd calls; these will be synthesized in large enough quantities to go into all relevant assays in parallel, cutting almost 4 weeks off the testing time.

Regular track: Concomitantly, we aim to push around 400-600 compounds through the regular cascade, which staggers the scale-up synthesis and PK until after protease assays (see Ed’s post). The first batch is already with Enamine.

We plan to fast-track the compounds with the following attributes:

  • They are designed to be covalent, building on the observed covalent hits
  • They recapitulate precisely the largest number of the observed fragment-protein interactions, from across all fragments.

The ask:

  • If you are submitting multiple molecules, please flag which submission you are most confident about. In particular, we would be grateful to know any chemical rationale.
  • Please provide the fragments that inspired you.
  • Preferably: copy-paste the URL from a Fragalysis snapshot (click on “share snapshot”)
  • Please comment on the submitted compounds on the forum. This will help us decide which compounds to fast-track.

We will try to decide on and announce the fast-tracked molecules within 48h.

See Nir’s post for covalent warheads that we think are the most practical.

Hi Alpha,

I have some input to the assay cascade discussions that may be useful.

I believe that you do need to include affinity measurement in the cascade since you can get useful SAR from compounds that bind too weakly to be observed meaningfully in the protease assay. The affinity measurements are likely to have the greatest impact early in the lead identification phase of the project.

With respect to covalently-bound inhibitors, you and the other members of the project management/leadership group do need to think very carefully about whether you want reversible inhibitors or irreversible inhibitors. My advice would be to go for reversible inhibitors and, while irreversible inhibitors are certainly tractable, you do need to be fully aware all the implications of going down this path. I have posted in connection with this issue in the TPP section and I’d suggest that you take a look at those comments (as well as Chris Bayly’s comments in the same section). I have also written some notes on reversibility in the context of cysteine protease inhibition:

I hope that this input is helpful and please be in touch if you’d like to discuss in more detail.