Discovery of potent molecular chimera (CM358) to treat human metastatic melanoma

• Published in: European journal of medicinal chemistry Vol. 138; pp. 602 - 615
• Main Authors: Gilad, Y., Tuchinsky, H., Ben-David, G., Minnes, R., Gancz, A., Senderowitz, H., Luboshits, G., Firer, M.A., Gellerman, G.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 29-09-2017
• Subjects: Animals; Anticancer drugs; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Chimeric compounds; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug conjugation; Drug Discovery; Drug Screening Assays, Antitumor; Drugs combination; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Human metastatic melanoma; Humans; Melanoma - drug therapy; Melanoma - pathology; Mice; Mice, Nude; Models, Molecular; Molecular docking; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Chimeric compounds; Anticancer drugs; Drugs combination; Molecular docking; Drug conjugation; Human metastatic melanoma
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.066

The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB). It demonstrates significant enhanced cytotoxicity over an equimolar mixture of AM and CLB in various cancer cell lines and in a xenograft model of human metastatic melanoma. Topo II inhibition as well as in silico docking studies suggest that CM358 is a stronger Topo II binder than AM. This may be attributed, at least partially, to the placement of the CLB moiety in a favorable orientation with respect to DNA cross-linking with nearby guanines. In a human metastatic melanoma (WM 266-4) xenograft model, this compound was profoundly superior to a mixture of AM and CLB in reduction of tumor growth, maintenance of body weight and extension of overall survival.
[Display omitted]
•Molecular chimera 1 (CM358) of chlorambucil and amonafide was discovered.•1 was effective in a human metastatic melanoma xenograft model.•1 was a stronger Topo II binder than AM.•1 rapidly induced necrosis of melanoma cells.•1 induced G2/M and S phases cell cycle arrest.