No abstract

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines. KEYWORDS: discoidin domain receptor, fragment-based drug design, back to front kinase design D iscoidin domain receptors, DDR1 and DDR2, are transmembrane receptor tyrosine kinases that are activated by collagen binding to their extracellular domain. 1,2 DDR1 and DDR2 have been associated with extracellular remodeling, cell adhesion, proliferation and migration, and they have been linked to a number of human diseases, including fibrotic disorders, atherosclerosis and cancer. 3−5 There has recently been evidence suggesting that DDR2 inhibitors would be useful for the treatment of lung squamous cell cancer 6,7 although the role of DDR2 may be more complex than first realized. 8−10 Hammerman et al. 6,7 have shown that DDR2 is mutated in approximately 4% of lung squamous cell cancer and have presented data to suggest that these are gain of function mutations. Hammerman et al. 6 have also shown that cell lines harboring these mutations are selectively sensitized through knockdown of DDR2 by RNA interference or by treatment of the multitargeted kinase inhibitor dasatinib. 11 Selective DDR2 inhibitors would therefore be useful to probe the role of DDR2 and may have utility for the treatment of lung cancer. To date, most DDR1/2 inhibitors have been derived from cross-screening of existing kinase inhibitors. 12 Initial compounds often lacked selectivity over homologous enzymes such as Bcr-Abl, but a number of recent papers have described more selective inhibitors which all bind to the DFG-out form of the enzyme. 13−15 Gray and co-workers have identified DDR1/2 inhibitors by screening a library of compounds that had previously been designed by mixing and matching motifs from known Type II kinase inhibitors. 14 The resulting compounds were reported to be selective with IC 50 values versus DDR1 and DDR2 of approximately 100 nM, and experimental binding modes in DDR1 were determined. 14,16 Gao et al. have published a series of potent Type II DDR1 inhibitors that are selective over other kinases, including DDR2. 13 In this Letter we describe a fragment based approach to the discovery of potent and selective DDR1/2 inhibitors. We first obtained a soakable crystal form of DDR1 suitable for high-throughput cry...

Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).

Rhodium-bound nitrenoids are trapped by tethered allenes generating acyloxy-enamines, aminocyclopropanes, and methylene aziridines. The aminocyclopropanes undergo substitution of the acetoxy group by a variety of nucleophiles.

Lp-PLA has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.