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.

Approved

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.