Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

Abstract

Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

Docking‐based In Silico Screening for Identification of Micromolar Inhibitors of Tropomyosin‐related Kinase A from Natural Origin

“…Note here that the carbonyl oxygen of 1 receives a hydrogen bond from the amidic nitrogen of backbone Met592 while the vicinal phenolic –OH moiety of 1 donates to the aminocarbonyl oxygen of Met592. The bidentate binding with Met592 through two hydrogen bonds is consistent with the previously reported X‐ray crystallographic analyses of TrkA‐inhibitor complexes, where the capability of making the multiple hydrogen bonds with the backbone groups of Met592 was found to play a central role in stabilization of the potent inhibitors within the ATP‐binding site …”

“…The X‐ray structure of TrkA in complex with a potent ATP‐competitive inhibitor involving the 4‐aminopyrazolylpyrimidine moiety (PDB entry: 4AOJ) was selected as the receptor model for molecular docking‐based virtual screening. The atomic coordinates of missing residues were obtained by using the homology modeling with the latest MODELLER software .…”

Identification of potent Yes1 kinase inhibitors using a library screening approach

“…Nonetheless, the compounds did bind to the ATP-binding pocket of the active conformation Yes1 homology model with little energy minimization required (Figure 5). The docking model of AZ-23 ( 8 ) to Yes1 was generated by superimposing the crystal structure of Trk kinase with AZ-23 bound (PDB ID: 4AOJ), 47 followed by a series of energy minimizations with the heavy atoms and backbone atoms fixed or tethered. Neither the protein nor the ligand experienced significant changes to reach the energetically minimized complex structure (Figure 5, A).…”

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

“…139 In the co-crystal structure of compound 1-3 with TRKA ( Figure 4B), TRKA is found in an inactive conformation with the C-helix pushed into a non-catalytically active orientation. 141 Compound 1-3 forms two hydrogen bonds at the hinge region with the pyrazole-moiety, and interacts with the amide backbone of Glu590 and Met592. The isopropoxy group is oriented toward Phe589, which is the gatekeeper amino acid.…”