Abstract
We describe a ligand-based approach towards compounds with more specific targeting for Burkitt’s lymphoma. Using three-dimensional ligand-based similarity searches and a previously described hit compound, we have identified six compounds that are chemically different but with similar spatial conformations. Biological evaluation revealed that one compound has better growth inhibition and improved selectivity towards Burkitt’s lymphoma cells than the query compound. However, initial mechanism-of-action studies show a different target profile in comparison with the previous hit compound, which does not involve the inhibition of the proteasome or the NFκB pathway. The data from this study provide a solid basis for further efforts in the search for selective agents against Burkitt’s lymphoma.
Highlights
Burkitt’s lymphoma is considered to be one of the clinically most aggressive of B-cell lymphomas.It is characterized by a translocation of the proto-oncogene c-Myc and immunoglobulin promoterMolecules 2014, 19 regions, which leads to constitutive expression of the MYC protein [1,2]
We demonstrated that compounds with the N-amidinopiperidine moiety are selectively cytotoxic towards malignantly transformed B-cells (Ramos and Daudi Burkitt’s lymphoma cells)
Direct comparisons of virtual screening data of several structure-based virtual screening campaigns revealed that a ligand-based ranking method (e.g., rapid overlay of chemical structures (ROCS)) performs at least as well as, and often even better than, docking methods [11]
Summary
Burkitt’s lymphoma is considered to be one of the clinically most aggressive of B-cell lymphomas.It is characterized by a translocation of the proto-oncogene c-Myc and immunoglobulin promoterMolecules 2014, 19 regions, which leads to constitutive expression of the MYC protein [1,2]. Burkitt’s lymphoma is considered to be one of the clinically most aggressive of B-cell lymphomas. It is characterized by a translocation of the proto-oncogene c-Myc and immunoglobulin promoter. Burkitt’s lymphoma most commonly affects children (representing 30%–50% of childhood non-Hodgkin’s lymphomas) and young adults. If left untreated, this disease is rapidly fatal, as it progresses extremely fast (doubling time, 24–48 h), and it has a high propensity to metastasize into the central nervous system [3]. Therapeutic intervention is initiated immediately, as it is accepted that the high growth fraction and the short doubling time of Burkitt’s lymphoma make intensive short-cycle chemotherapy a necessity. Due to the intense chemotherapy, there are often acute cytotoxic effects, including neutropenia, thrombocytopenia, myelosuppression, nausea and vomiting, neurotoxicity, hyperglycemia, stomach problems, cardiotoxicity, hair loss, constipation, and hypotension [3,5,7]
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