The First ATP Competitive Type-III c-MET Inhibitor?

TypeIII c met inhib

In this paper, the target was c-MET, which is a receptor tyrosine kinase implicated in the development of tumour cells. Hyperactivation of c-MET is associated with poor prognoses in cancer patients, including tumour survival and metastasis. Existing inhibitors of c-MET are clustered into types, depending on their site of binding and mode of action. Type I inhibitors have run into efficacy problems caused by clinically relevant c-MET mutants that are able to evade inhibition. Type II inhibitors bind to the active site of c-MET, and are active against mutants, however, they do suffer from non-selective kinase inhibition and suboptimal PK properties. The latter point being important for brain penetrant c-MET inhibitors, which is where the unmet clinical need was found.

A fragment screen was undertaken against WT and D1228V c-MET, which afforded a hit compound that displayed an IC50 of ~2 μM (for both constructs) that was competitive with adenosine – suggesting that the hit was binding at the active site. It was then found, after obtaining the crystal structure of the hit with D1228V c-MET, that the ligand was residing in the back pocket. Concurrent with ligand binding at this site, was the allosteric closure of the ATP (active site) pocket, nicely explaining the observed adenosine competition.

There followed a structure-enabled hit-to-lead campaign that made heavy use of binding site and water network analysis tools. Following the strategy of displacing unstable water molecules with polar groups lead to several jumps in potency, however, due to the requirement for CNS penetration, the tPSA had to be kept under control. FEP-guided optimisation of potency allowed the authors to push this series into lead optimisation, during which, an acetylene group was installed as an isosteric replacement for CN that actually relatively improved the metabolic profile. Reasonable permeabilities and unbound brain-to-plasma (Kp,uu) values piqued further interest in this series.

Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor

J. Med. Chem. 2023, 66, 13, 8782–8807