Design, Synthesis, and Biological Evaluation of Potent c-Met Inhibitors

Abstract

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

“…Other structural studies of mutant c-Met kinase domains bound with inhibitors have also employed multiple mutations in the activation loop selected from single-point oncogenic mutations (20,21). In these cases, the activation loop is disordered, as seen here upon phosphorylation, and formally consistent with the use of naturally occurring activating mutations.…”

“…In these cases, the activation loop is disordered, as seen here upon phosphorylation, and formally consistent with the use of naturally occurring activating mutations. However, helix ␣C in the mutant structures (6,20,21) does not adopt the active orientation seen here for autophosphorylated c-Met. In the case of the ligand-bound mutant structures (19,20), apo structures of the c-Met mutants have not been reported, so it is unknown whether the inhibitor induces the inactive helix ␣C conformation or that the orientation of helix ␣C results from the presence of the multiple mutations.…”

Small molecule c-Met kinase inhibitors: a review of recent patents

“…Pyridine 45 is claimed to have a K i of 6 nM in a c-Met kinase assay; HUVEC proliferation assays and a rat corneal neovascularisation model are among the other biological screens described although no data are given. The SAR and crystal structure of the related pyrimidones, for example, 46, have been described [87].…”

Discovery of Novel c-Met Inhibitors Bearing a 3-Carboxyl Piperidin-2-one Scaffold

“…Replacement of the 6,7-dimethoxyquinoline moiety by various N-containing heterocycles, such as substituted quinoline [12], thienopyridine [13][14][15], pyrrolopyridine [16], aminopyridine [17], thienopyrimidine [18], furopyrimidine [18], imidazopyridine [19] or imidazopyridazine [19], has been investigated. The bridge moiety B connecting moiety A and C was designed as linear [20][21][22] or cyclic [14,15,[23][24][25][26], bearing at least one amide bond with 5-atoms in the main chain [22,24] (i.e., six chemical bonds distance between moiety A and C, Figure 1). However, there are little changes to moiety A and C, except for phenyl ring or substituted phenyl ring modifications to the former.…”