Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy

Abstract

MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.

Synthetic Approaches to the New Drugs Approved During 2022

“…Savolitinib ( 20 ) is a small molecule inhibitor of the mesenchymal epithelial transition factor (MET) oncogene and was conditionally approved in China in 2021 for treatment of patients with nonsmall cell lung cancer with MET exon 14 skipping mutations . This mutation results in increased MET stability and expression which results in prolongation of multiple downstream signaling pathways that regulate key cellular functions including proliferation, differentiation, and cell survival .…”

Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning

“…As an example of the insights that can be learned from the inhibitor DMS screens, we examined the profile for crizotinib, one of four FDA approved inhibitors for MET and a multitarget TKI (Cui et al, 2011;Wang and Lu, 2023;Santarpia et al, 2021). To identify mutations that show gain-of-function and loss-of-function behaviors specific to inhibitors compared to DMSO, we subtracted DMSO from all fitness scores.…”

“…However, without extensive documentation of the behavior of resistance and sensitizing mutations in MET towards specific TKIs, there remains a barrier towards leveraging inhibitors for specific mutational responses, optimizing inhibitor pairings, and informing rational drug design. Thousands of compounds have been screened against the MET kinase domain, and while several have undergone clinical trials, currently four MET inhibitors have received FDA approval: crizotinib, cabozantinib, tepotinib, and capmatinib (Santarpia et al, 2021;Wang and Lu, 2023). Nevertheless, the emergence of resistance not only limits the efficacy of these drugs but also poses challenges for second-line therapeutic strategies, particularly in the context of rare and novel mutations.…”

Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment

“…Cellular-mesenchymal epithelial transition factor (c-Met) is an effective target in cancer treatment and c-Met inhibitors have been successively launched for the treatment of solid tumors such as lung cancer and kidney cancer . c-Met inhibitors are mainly divided into three categories (types I, II, and III; see Figure ) according to their binding patterns with the c-Met kinase domain . Based on the interaction with residue G1163 near the solvent region, type I inhibitors can be further divided into type Ia (crizotinib) and Ib (capmatinib, tepotinib, and savolitinib).…”

“…Based on the interaction with residue G1163 near the solvent region, type I inhibitors can be further divided into type Ia (crizotinib) and Ib (capmatinib, tepotinib, and savolitinib). Type Ia inhibitors have hydrophobic interactions with G1163, while type Ib inhibitors bind to the kinase domain independently of this interaction, making them more selective than type Ia inhibitors. − Type II inhibitors (cabozantinib, foretinib) generally refer to multitarget kinase inhibitors, while type III inhibitors (tivantinib) refer to allosteric inhibitors …”