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
MK-8931 Merck BACE1 inhibitor
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
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.