15 July 2016

Fragments in the clinic: 2016 edition

There’s a new FBDD review out today in Nat. Rev. Drug Discovery. I know - there are lots of reviews each year - but this one is written by a who's who list of luminaries, including Steve Fesik (Vanderbilt), Rod Hubbard (Vernalis and University of York),  Wolfgang Jahnke (Novartis), and Harren Jhoti (Astex). I'm also an author so I'm undoubtedly biased, but I think it provides a nice overview of the field, especially for those who don't have time to read the recent book.

The review distills hard-won wisdom from two decades of work and covers practical decisions needed when using fragments: library design, screening methods, protein-ligand interactions, hit to lead strategies, and applications. Another useful feature is what I believe to be the most complete and up-to-date list of fragment-derived drugs that have entered clinical development. Where possible these include chemical structures, so definitely check it out.

The drugs themselves are listed below. Although it has not even been two years since the last compilation, it is exciting to see several promotions and new entrants. This table includes compounds whether or not they are still in development (indeed, some of the companies no longer even exist). A few compounds from earlier lists have been removed because their fragment origins could not be confirmed. Drugs reported as still active in clinicaltrials.gov, company websites, or other sources are in bold, and those that have been discussed on Practical Fragments are hyperlinked to the most relevant post.


Drug Company Target
Approved!

Vemurafenib Plexxikon B-Raf(V600E)
Venetoclax AbbVie/Genentech Selective Bcl-2
Phase 3

PLX3397 Plexxikon FMS, KIT, and FLT-3-ITD
Verubecestat Merck BACE1
AZD3293 AstraZeneca/Astex/Lilly BACE1
Phase 2

AT7519 Astex CDK1,2,4,5,9
AT9283  Astex Aurora, JAK2
AZD5363 AstraZeneca/Astex/CR-UK AKT
Erdafitinib J&J/Astex FGFR1-4
Indeglitazar Plexxikon pan-PPAR agonist
LY2886721 Lilly BACE1
LY517717 Lilly/Protherics FXa
Navitoclax (ABT-263) Abbott Bcl-2/Bcl-xL
NVP-AUY922 Vernalis/Novartis HSP90
Onalespib Astex HSP90
Phase 1

ABL001 Novartis BCR-ABL
ABT-518AbbottMMP-2 & 9
ABT-737AbbottBcl-2/Bcl-xL
ASTX660 Astex XIAP/cIAP1
AT13148AstexAKT, p70S6K, ROCK
AZD3839AstraZenecaBACE1
AZD5099AstraZenecaBacterial topoisomerase II
BCL201 Vernalis/Servier/Roche BCL-2
DG-051deCODELTA4H
IC-776Lilly/ICOSLFA-1
LP-261LocusTubulin
LY2811376LillyBACE1
PF06650833 Pfizer IRAK4
PLX5568Plexxikonkinase
SGX-393SGXBCR-ABL
SGX-523SGXMet
SNS-314SunesisAurora

The current list contains more than 30 clinical-stage drugs but is certainly incomplete, particularly in Phase I. If you know of any others (and can mention them) please leave a comment.

3 comments:

Anonymous said...

What happened to Novartis and Astex's ribociclib/Lee011?

Was on the 2015 list, but is not on the 2016 list. Now approved.

Dan Erlanson said...

Good catch anonymous. Closer investigation revealed that FBLD really didn't play a role in the discovery of ribociclib - sorry for the earlier confusion.

Dan Erlanson said...

ABBV-075, a BRD4 inhibitor, is in Phase I. Some of the early work is described here.