Supplemental Digital Content is available in the text.,The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoints are negative regulators of T-cell immune function.,Inhibition of these targets, resulting in increased activation of the immune system, has led to new immunotherapies for melanoma, non-small cell lung cancer, and other cancers.,Ipilimumab, an inhibitor of CTLA-4, is approved for the treatment of advanced or unresectable melanoma.,Nivolumab and pembrolizumab, both PD-1 inhibitors, are approved to treat patients with advanced or metastatic melanoma and patients with metastatic, refractory non-small cell lung cancer.,In addition the combination of ipilimumab and nivolumab has been approved in patients with BRAF WT metastatic or unresectable melanoma.,The roles of CTLA-4 and PD-1 in inhibiting immune responses, including antitumor responses, are largely distinct.,CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T cells later in an immune response, primarily in peripheral tissues.,The clinical profiles of immuno-oncology agents inhibiting these 2 checkpoints may vary based on their mechanistic differences.,This article provides an overview of the CTLA-4 and PD-1 pathways and implications of their inhibition in cancer therapy.
Epigenetic proteins are intently pursued targets in ligand discovery.,To date, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic “writers” and “erasers”.,Potent inhibitors of histone binding modules have not yet been described.,Here we report a cell-permeable small molecule (JQ1) which binds competitively to acetyl-lysine recognition motifs, or bromodomains.,High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity.,Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma.,Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific anti-proliferative effects in BRD4-dependent cell lines and patient-derived xenograft models.,These data establish proof of concept for targeting protein-protein interactions of epigenetic “readers” and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.