02 January 2013

Fragments in the clinic: 2013 edition

It’s been more than two years since Practical Fragments updated its list of fragment-derived compounds in the clinic, and a lot has changed since then – mostly for the better. The latest list is inspired by a fantastic news article in Nature Review Drug Discovery that quotes a wide range of fragment-practitioners and outside experts. It’s a fun, fast read, so definitely check it out. It also includes a handy table of late-stage fragment-derived clinical compounds, their ClogPs, and their molecular weights, along with those of the initial fragment hits.

The list below borrows from this table and also includes molecules from other sources, whether or not they are still in development (indeed, some of the originator companies no longer exist). Those listed as still active in clinicaltrials.gov or company websites are in bold, and those that have been covered in Practical Fragments are hyperlinked to the relevant post.


Vemurafenib (PLX4032)        Plexxikon         B-Raf(V600E) inhibitor

Phase 2/3

MK-8931                                Merck              BACE1 inhibitor

Phase 2

AT13387                                 Astex              HSP90 inhibitor
AT7519                                   Astex              CDK1,2,4,5 inhibitor
AT9283                                   Astex              Aurora, Janus kinase 2 inhibitor
AUY922                         Vernalis/Novartis      HSP90 inhibitor
Indeglitazar                             Plexxikon         pan-PPAR agonist
Linifanib (ABT 869)                Abbott             VEGF & PDGFR inhibitor
LY2886721                             Lilly                 BACE1 inhibitor
LY517717                        Lilly/Protherics          FXa inhibitor
Navitoclax (ABT 263)              Abbott             Bcl-2/Bcl-xL inhibitor
PLX3397                                 Plexxikon        FMS, KIT, and FLT-3-ITD inhibitor

Phase 1

ABT-518                                 Abbott             MMP-2 & 9 inhibitor
ABT-737                                 Abbott             Bcl-2/Bcl-xL inhibitor
AZD3839                                AstraZeneca     BACE1 inhibitor
AZD5363                        AstraZeneca/Astex  AKT inhibitor
DG-051                                  deCODE            LTA4H inhibitor
IC-776                                   Lilly/ICOS         LFA-1 inhibitor
JNJ-42756493                     J&J/Astex         FGFr inhibitor
LEE011                             Novartis/Astex      CDK4 inhibitor
LP-261                                   Locus               Tubulin binder
LY2811376                              Lilly                 BACE1 inhibitor
PLX5568                                 Plexxikon         kinase inhibitor
SGX-393                                 SGX                 Bcr-Abl inhibitor
SGX-523                                 SGX                 Met inhibitor
SNS-314                                 Sunesis            Aurora inhibitor

There are some interesting trends, such as the number of BACE1 inhibitors – a fact the Nat Rev Drug Disc piece also notes. This has been an immensely difficult target, so it’s nice to see fragment-based approaches deliver compounds to the clinic. Whether BACE1 inhibitors will ultimately prove useful for treating Alzheimer’s disease remains to be seen, but at least FBLD has provided the tools to test this hypothesis.

The current list contains 26 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.


@BioDueDiligence said...

Great list - thanks for updating. Astex has one more drug AT13148, an AGC Kinase inhibitor starting phase 1 trials in oncology.

Chris said...

Might be useful to have a link to this list in the sidebar?

Dan Erlanson said...

Good idea Chris - this post now has a link on the sidebar for easier access.

Thanks BioDueDiligence for the tip on AT13148.

I just came across a selective Abbott Bcl-2 inhibitor, ABT-199, in Phase 1b:


Dan Erlanson said...

Here's the press release for AT13148:


Dan Erlanson said...

Vernalis and Servier recently announced that their BCL-2 inhibitor has entered Phase I:


Anonymous said...

last time i checked AZD5363 is now in phase 2. and it isnt really an astex compound, rather it came from the CR-UK/ICR side of the collaboration.