Discovery of Pyrrolopyridine−Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities

Abstract

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

A Drug Resistance Screen Using a Selective MET Inhibitor Reveals a Spectrum of Mutations That Partially Overlap with Activating Mutations Found in Cancer Patients

“…This is why, in the absence of an available cocrystal structure of AMG 458 and MET, we modeled the binding mode of the inhibitor (Fig. 3B) using the reported crystal structure of MET in complex with a type II pyrrolopyridine-pyridone inhibitor of similar chemical structure (25). This model provides a plausible and simple explanation to the appearance of mutations at residues Y1159, G1163, M1211, V1155, L1195, and F1200 in the resistance screen.…”

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

“…In contrast, there is open space facing the solvent-exposed space when compounds bind with the "flipped" binding mode, and this would bring a significant preference for binding orientation of 2-substituted azaindoles. Compounds 12-16 also bind to kinases with the "flipped" orientation [24][25][26][27][28] ; these compounds are type II kinase inhibitors, which can interact with a deep allosteric pocket created by conformational change in the activation loop that adopts the inactive-DFG-out conformation. Almost all 7-azaindoles with "normal" binding modes are type I kinase inhibitors except one ligand (PDB code, 3ETA), suggesting that there might be some relation between binding orientation of azaindole and type of kinase inhibitors.…”

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

“…Generally, structural optimization based on compound 1 mainly focused on moiety D and B. 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).…”