RESUMO
Natural killer group 2, member D (NKG2D) receptor is a crucial activating receptor in the immune recognition and eradication of abnormal cells by natural killer (NK) cells, and T lymphocytes. NKG2D can transmit activation signals and activate the immune system by recognizing the NKG2D ligands (NKG2D-L) on acute myeloid leukemia (AML) cells. Downregulation of NKG2D-L in AML can circumvent resistance to chemotherapy and immune recognition. Considering this effect, the exploration of targeting the NKG2D/NKG2D-L axis is considered to have tremendous potential for the discovery of novel biomacromolecule antibodies and pharmacological modulators in AML. This review was to outline the impact of NKG2D/NKG2D-L axis on intrinsic immunosurveillance and the development of AML. Furthermore, the NKG2D/NKG2D-L axis related modulators and progress in preclinical and clinical trials was also to be reviewed.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Animais , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Ligantes , Terapia de Alvo Molecular , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
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.