RESUMO
Generating inhibitors for A Disintegrin And Metalloproteinase 10 (ADAM10), a zinc-dependent protease, was heavily invested in by the pharmaceutical industry starting over 20 years ago. There has been much enthusiasm in basic research for these inhibitors, with a multitude of studies generating significant data, yet the clinical trials have not replicated the same results. ADAM10 is ubiquitously expressed and cleaves many important substrates such as Notch, PD-L1, EGFR/HER ligands, ICOS-L, TACI, and the "stress related molecules" MIC-A, MIC-B and ULBPs. This review goes through the most recent pre-clinical data with inhibitors as well as clinical data supporting the use of ADAM10 inhibitor use in cancer and autoimmunity. It additionally addresses how ADAM10 inhibitor therapy can be improved and if inhibitor therapy can be paired with other drug treatments to maximize effectiveness in various disease states. Finally, it examines the ADAM10 substrates that are important to each disease state and if any of these substrates or ADAM10 itself is a potential biomarker for disease.
Assuntos
Proteína ADAM10/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Ensaios Clínicos como Assunto , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Estudos Multicêntricos como Assunto , Neoplasias/enzimologia , Neoplasias/imunologia , Inibidores de Proteases/farmacologia , Receptores Notch/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade por SubstratoRESUMO
Hodgkin's lymphoma (HL) is the most common malignant lymphoma in young adults in the western world. This disease is characterized by an overexpression of ADAM-10 with increased release of NKG2D ligands, involved in an impaired immune response against tumor cells. We designed and synthesized two new ADAM-10 selective inhibitors, 2 and 3 based on previously published ADAM-17 selective inhibitor 1. The most promising compound was the thiazolidine derivative 3, with nanomolar activity for ADAM-10, high selectivity over ADAM-17 and MMPs and good efficacy in reducing the shedding of NKG2D ligands (MIC-B and ULBP3) in three different HL cell lines at non-toxic doses. Molecular modeling studies were used to drive the design and X-ray crystallography studies were carried out to explain the selectivity of 3 for ADAM-10 over MMPs.