G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Although G4s are attractive therapeutic targets, ligands capable of discriminating between different G4 structures are rare. Here, we describe DC-34, a small molecule that potently downregulates MYC transcription in cancer cells by a G4-dependent mechanism. Inhibition by DC-34 is significantly greater for MYC than other G4-driven genes. We use chemical, biophysical, biological, and structural studies to demonstrate a molecular rationale for the recognition of the MYC G4. We solve the structure of the MYC G4 in complex with DC-34 by NMR spectroscopy and illustrate specific contacts responsible for affinity and selectivity. Modification of DC-34 reveals features required for G4 affinity, biological activity, and validates the derived NMR structure. This work advances the design of quadruplex-interacting small molecules to control gene expression in therapeutic areas such as cancer.

are co-inventors on invention disclosures related to targeting PTPN22 to treat cancers, developing novel compounds against PTPN22, and/or utilizing rs2476601 as a predictive biomarker for cancer immunotherapy. W.H. is a co-inventor of patents with potential for receiving royalties from Rodeo Therapeutics unrelated to the current study. M.Y. reports receiving research grants from Incyte, Bristol-Myers Squibb, and Exelixis, and is a consultant for AstraZeneca, Eisai, Exelixis, and Genentech. E.J.F. is a consultant for Champions Oncology. B.H.P. had ownership interest and was a paid member of the scientific advisory board of Loxo Oncology and was a paid consultant for Foundation Medicine, Inc, Lilly, Casdin Capital and Roche. He is currently a paid scientific advisory board member of Celcuity and a paid consultant for Jackson Laboratories and Pathovax. Under separate licensing agreements

Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.