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

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
ASTX660 Astex XIAP/cIAP1
AT13148AstexAKT, p70S6K, ROCK
AZD5099AstraZenecaBacterial topoisomerase II
BCL201 Vernalis/Servier/Roche BCL-2
PF06650833 Pfizer IRAK4

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.


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.

Dan Erlanson said...

A few more clinical compounds derived from fragments, as heard at the 2018 CHI FBDD meeting, include:

Pfizer's PF-06835919, a KHK inhibitor in Phase 2

eFFECTOR's eFT508, an MNK1/2 inhibitor also in Phase 2

Genentech's GDC-0994, which entered Phase 1

Finally, fragments may have played a role in AbbVie's approved HCV drug dasabuvir

Dan Erlanson said...

Novartis has put a fragment-derived PRC EED inhibitor called MAK683 into the clinic; some of the earlier work is described here.

Dan Erlanson said...

At the recent ACS meeting Lilly disclosed their fragment-derived BACE1 inhibitor, which, in contrast to most other BACE1 inhibitors, appears to still be in the clinic.