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Replies to post #209558 on Biotech Values
I’ve very much been enjoying this paper, on fragment-based chemogenomics in whole cells. That’s the sort of blurb, I admit, that’s probably going to make you immediately want to read the rest of the paper, or immediately go do something else (all the way up to “podiatrist appointment”). And I understand those impulses. But if you’re into new targets and drug discovery, you had better read on. It’s quite a ride.
It’s a collaboration from the Cravatt group at Scripps, the University of Lausanne, Bristol-Myers Squibb, and the Salk Institute, and what they’re doing is, in a way, the more demanding follow-up to the covalent fragments work that’s been published before.
I’ll let the authors sum up:
We have described herein a chemical proteomic method to globally map small-molecule fragment-protein interactions directly in human cells. More than 2,000 fragment-binding proteins were discovered, only a small fraction of which was found in DrugBank, highlighting the broad and still largely untapped ligandability of the human proteome. We demonstrated that the discovered fragment-protein interactions can be further advanced to generate selective ligands that modulate the functions of proteins in cells. That the case studies investigated herein include enzymes (PTGR2), transporters (SLC25A20), and poorly characterized transmembrane proteins (PGRMC2) for which selective ligands were previously lacking, underscores the versatility and scope of chemical proteomics for accelerating the discovery of small-molecule probes for diverse categories of proteins.
Yes, yes it does. People have been using the photoaffinity/click combination for some time, but this is the biggest, widest application of it that I’ve yet seen, and it points the way into a huge amount of useful research. If you’re into phenotypic screening, difficult targets, and early-stage drug discovery in general, you have to pay attention to this work. Read it now! I’ve been saying for years that fragment-based screens and phenotypic screening are two worlds that never intersect, but here is the pathway between them. The fragment portion of the paper demonstrates that the compounds are engaged in real, meaningful, and often selective interactions with proteins in living cells, and the phenotypic screen in the latter half – the business ends of whose structures are still well within fragment parameters – show the power of this technique to identify useful, functional ligands.
This is one of the most interesting, useful, encouraging and thought-provoking chemical biology papers I’ve ever seen; it really does not get any better than this. You’d have to go to another planet and hope that someone over there is working at this level.
04/13/17 10:43 AM
Bristol-Myers Squibb Company today announced that it has entered into two separate agreements to license BMS-986168, an anti-eTau compound in development for Progressive Supranuclear Palsy (PSP), to Biogen, and BMS-986089, an anti-myostatin adnectin in development for Duchenne Muscular Dystrophy (DMD), to Roche.
…Biogen will pay to Bristol-Myers Squibb an upfront payment of $300 million with potential milestone payments of up to $410 million. Biogen also will assume all remaining obligations to the former stockholders of iPierian, Inc. related to Bristol-Myers Squibb’s acquisition of the company in 2014.
…Roche will pay to Bristol-Myers Squibb an upfront payment of $170 million with potential milestone payments of up to $205 million.
Bristol-Myers Squibb will receive tiered double-digit royalties if either asset is approved and commercialized.
